Pyrazole-Containing Macrophage Migration Inhibitory Factor Inhibitors

ABSTRACT

In one aspect, the invention comprises compounds that bind and inhibit macrophage migration inhibitory factor. In another aspect, the invention provides methods of treating inflammatory disease, neurological disorders and cancer using the compounds of the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional Patent Application No. 62/643,332, filed Mar. 15, 2018,which is hereby incorporated herein by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under GM032136 awardedby National Institutes of Health. The government has certain rights inthe invention.

BACKGROUND OF THE INVENTION

Human macrophage migration inhibitory factor (MIF) is a proinflammatorycytokine that is implicated in the pathogenesis of numerous inflammatorydiseases, neurological disorders, and cancer. MIF is expressed invarious cell types, and its tissue distribution is widespread. Uponactivation of cells such as macrophages, monocytes and T-cells,expression of MIF in turn activates release of inflammatory cytokinesincluding interleukins, interferon, and TNFα. Complex signaling pathwaysare invoked when MIF binds to its membrane-bound receptors CD74 andCXCR4, leading to leukocyte chemotaxis, inflammatory response, andpotential tissue damage. There is strong correlation between MIFexpression and the severity of many inflammatory and autoimmune diseasesincluding asthma, sepsis, lupus, and rheumatoid arthritis. For cancer,the AKT pathway may be activated by MIF binding causing suppression ofapoptosis by inhibition of the normal action of BAD, BAX, and p53.However, MIF's role in cancer is multifaceted with undesirable effectsalso on cell proliferation, angiogenesis, and metastasis; MIF isover-expressed in most human cancer cells.

Interestingly, MIF also shows enzymatic activity as a keto-enoltautomerase. MIF is a toroid-shaped, trimeric protein consisting of 342amino acid residues with three identical active sites occurring at theinterfaces of the monomer subunits. The active sites are relativelycylindrical and open to the surface of the protein in the vicinity ofProl, which serves as the catalytic base.

There is a need in the art for potent and specific inhibitors of MIF.Such compounds should be useful in the treatment of diseases anddisorders, such as but not limited to, inflammatory diseases,neurological disorders, and/or cancer. The present invention addressesthis need.

SUMMARY OF THE INVENTION

In one aspect the invention provides a compound of formula (I), or asalt, solvate, stereoisomer, or tautomer thereof, or any mixturesthereof:

wherein in (I): Y is selected from the group consisting of a bond,—CH₂—, —O—, —S—, —S(═O)—, —S(═O)₂, and —N(R₂)—; R₁ is selected from thegroup consisting of H, C₁-C₆ alkyl, phenyl, naphthyl,tetrahydronaphthyl, phenanthryl, bicyclic heteroaryl,1,2-dihydroacenaphthyl, acenaphthyl, adamantyl, (heteroaryl)-phenyl, andbiphenyl; R₂ is selected from the group consisting of H and C₁-C₆ alkyl;Z is selected from the group consisting of —COOR, —S(═O)R, —S(═O)₂R, andSO₂NRR; X is selected from the group consisting of H, C₁-C₃ alkyl, andhalogen; wherein the phenyl, naphthyl, tetrahydronaphthyl, phenanthryl,bicyclic heteroaryl, 1,2-dihydroacenaphthyl, acenaphthyl, adamantyl,(heteroaryl)-phenyl, or biphenyl is independently optionally substitutedwith at least one group independently selected from the group consistingof halogen, —OH, —C(═O)OR, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆halocycloalkyl, C₃-C₆ halocycloalkoxy, —(CH₂)₁₋₆NRR, —O(CH₂)₁₋₆NRR,—(CH₂)₁₋₆NR(C₁-C₆ acyl), —O(CH₂)₁₋₆NR(C₁-C₆ acyl), —(CH₂)₁₋₆OR,—O(CH₂)₁₋₆OR, —(CH₂)₁₋₆C(═O)OR, —O(CH₂)₁₋₆C(═O)OR, —(CH₂)₁₋₆OR,—O(CH₂)₁₋₆OR, —(OCH₂CH₂)₁₋₆NRR, and —(OCH₂CH₂)₁₋₆C(═O)OR; wherein eachoccurrence of R is independently selected from the group consisting of Hand C₁-C₆ alkyl, or two R groups combine with the N atom to which theyare both bound to form a 3-8 membered heterocyclyl or heteroaryl group(such as, but not limited to, piperidinyl, morpholinyl, pyrrolidinyl,pyridinyl, imidazolyl, and the like); and wherein if R₁—Y is H, then Zcannot be —COOH.

In various embodiments, the compound of formula (I) is a compound offormula (6):

In various embodiments, R₁ is selected from the group consisting ofphenyl and naphthyl.

In various embodiments, the compound is selected from the groupconsisting of: 6a, 4-(1H-pyrazol-4-yl)-[1,1′-biphenyl]-2-carboxylicacid; 6b, 2-(Naphthalen-1-yl)-5-(1H-pyrazol-4-yl)benzoic acid; 6c,2-(Naphthalen-2-yl)-5-(1H-pyrazol-4-yl)benzoic acid; 9a, methyl3-(1H-pyrazol-4-yl)benzoate; 9b,4-(3-(methylsulfonyl)phenyl)-1H-pyrazole; 9c,4-(3-(methylsulfonyl)phenyl)-1H-pyrazole; 9d,N-methyl-3-(1H-pyrazol-4-yl)benzenesulfonamide; 9e,2-methyl-5-(1H-pyrazol-4-yl)benzoic acid.

In various embodiments, the compound of formula (I) is a compound offormula (7):

In various embodiments, R₁ is selected from the group consisting ofphenyl and naphthyl.

In various embodiments, R₂ is methyl.

In various embodiments, the compound of formula 7 is selected from thegroup consisting of: 7a, 2-(Phenylamino)-5-(1H-pyrazol-4-yl)benzoicacid; 7b, 2-(Methyl(naphthalen-2-yl)amino)-5-(1H-pyrazol-4-yl)benzoicacid.

In various embodiments, the compound of formula (I) is a compound offormula (8):

In various embodiments, R₁ is selected from the group consisting ofmethylphenyl, methoxyphenyl, fluorophenyl, ethylnapthyl,cyclopropylnaphthyl, methylbiphenyl, ethoxybiphenyl andN-morpholinopropoxybiphenyl.

In various embodiments, X is fluorine.

In various embodiments, the compound of formula 8 is selected from thegroup consisting of: 8a, 2-Phenoxy-5-(1H-pyrazol-4-yl)benzoic acid; 8b,5-(1H-Pyrazol-4-yl)-2-(o-tolyloxy)benzoic acid; 8c,5-(1H-Pyrazol-4-yl)-2-(m-tolyloxy)benzoic acid; 8d,5-(1H-Pyrazol-4-yl)-2-(p-tolyloxy)benzoic acid; 8e,2-(3-Fluorophenoxy)-5-(1H-pyrazol-4-yl)benzoic acid; 8f,2-(4-Fluorophenoxy)-5-(1H-pyrazol-4-yl)benzoic acid; 8g,2-(Naphthalen-2-yloxy)-5-(1H-pyrazol-4-yl)benzoic acid; 8h,4-(3-(Methylsulfonyl)-4-(naphthalen-2-yloxy)phenyl)-1H-pyrazole; 8i,2-(Naphthalen-2-yloxy)-5-(1H-pyrazol-4-yl)benzenesulfonamide; 8j,2-(Phenanthren-9-yloxy)-5-(1H-pyrazol-4-yl)benzoic acid; 8k,2-((Adamantan-2-yl)oxy)-5-(1H-pyrazol-4-yl)benzoic acid; 8l,2-((1,2-Dihydroacenaphthylen-4-yl)oxy)-5-(1H-pyrazol-4-yl)benzoic acid;8m, 5-(3-Fluoro-1H-pyrazol-4-yl)-2-(naphthalen-1-yloxy)benzoic acid; 8n,5-(3-Fluoro-1H-pyrazol-4-yl)-2-(naphthalen-2-yloxy)benzoic acid; 8o,2-((4-Ethylnaphthalen-2-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoicacid; 8p,2-((5-Ethylnaphthalen-2-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoicacid; 8q,2-((7-Ethylnaphthalen-2-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoicacid; 8r,2-((4-Cyclopropylnaphthalen-2-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoicacid; 8s,2-((4-Cyclopropyl-7-ethylnaphthalen-2-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoicacid; 8t,2-([1,1′-Biphenyl]-4-yloxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoic acid;8u, 2-([1,1′-Biphenyl]-3-yloxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoicacid; 8v,2-((3′,5′-Dimethyl-[1,1′-biphenyl]-3-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoicacid; 8w,2-((4′-Ethoxy-[1,1′-biphenyl]-3-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoicacid; 8x,5-(3-Fluoro-1H-pyrazol-4-yl)-2-((4′-(3-morpholinopropoxy)-[1,1′-biphenyl]-3-yl)oxy)benzoicacid; 9f, 2-(3-chlorophenoxy)-5-(1H-pyrazol-4-yl)benzoic acid; 9g,2-(4-chlorophenoxy)-5-(1H-pyrazol-4-yl)benzoic acid; 9h,2-(4-methoxyphenoxy)-5-(1H-pyrazol-4-yl)benzoic acid; 9i,2-(3-methoxyphenoxy)-5-(1H-pyrazol-4-yl)benzoic acid; 9j,2-(4-(aminomethyl)phenoxy)-5-(1H-pyrazol-4-yl)benzoic acid; 9k,2-(3-(aminomethyl)phenoxy)-5-(1H-pyrazol-4-yl)benzoic; 9l,2-(4-(2-acetamidoethyl)phenoxy)-5-(1H-pyrazol-4-yl)benzoic acid; 9m,2-(benzofuran-7-yloxy)-5-(1H-pyrazol-4-yl)benzoic acid; 9n,2-(3-carboxyphenoxy)-5-(1H-pyrazol-4-yl)benzoic acid; 9o,2-(benzofuran-5-yloxy)-5-(1H-pyrazol-4-yl)benzoic acid; 9p,2-(benzofuran-6-yloxy)-5-(1H-pyrazol-4-yl)benzoic acid; 9q,2-(acenaphthylene-4-yloxy)-5-(1H-pyrazol-4-yl)benzoic acid; 9r,2-(phenylsulfinyl)-5-(1H-pyrazol-4-yl)benzoic acid; 9s,2-(benzofuran-6-yloxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoic acid; 9t,5-(3-fluoro-1H-pyrazol-4-yl)-2-(3-fluorophenoxy)benzoic acid; 9u,2-((7-methylnaphthalen-2-yl)oxy)-5-(1H-pyrazol-4-yl)benzoic acid; 9v,2-((1,2-dihydroacenaphthylen-4-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoicacid; 9w, 5-(3-fluoro-1H-pyrazol-4-yl)-2-(3-(trifluoromethyl)phenoxy)benzoic acid; 9x,2-((7-cyclopropylnaphthalen-2-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoicacid; 9y,5-(3-fluoro-1H-pyrazol-4-yl)-2-((5,6,7,8-tetrahydronaphthalen-2-yl)oxy)benzoicacid; 9z,2-((5-cyclopropylnaphthalen-2-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoicacid; 9aa,5-(3-fluoro-1H-pyrazol-4-yl)-2-(3-(pyrimidin-2-yl)phenoxy)benzoic acid;9bb,5-(3-fluoro-1H-pyrazol-4-yl)-2-44′-(2-morpholinoethyl)-[1,1′-biphenyl]-3-yl)oxy)benzoicacid; 9cc, 5-(3-methyl-1H-pyrazol-4-yl)-2-(naphthalen-2-yloxy)benzoicacid.

In various embodiments, the invention provides a pharmaceuticalcomposition comprising at least one compound of the invention and atleast one pharmaceutically acceptable excipient.

In various embodiments, the invention provides a method of treating aninflammatory disease, a neurological disorder, and/or cancer in asubject in need thereof, the method comprising administering to thesubject an effective amount of the compounds and/or the pharmaceuticalcompositions of the invention.

In various embodiments, the inflammatory disease is rheumatoidarthritis, Crohn's disease, or inflammatory bowel syndrome.

In various embodiments, the neurological disorder is schizophrenia.

In various embodiments, the cancer is colorectal, lung, breast, orprostate.

In another aspect, the invention provides a method of inhibitingmacrophage migration inhibitory factor in a subject in need thereof, themethod comprising administering to the subject an effective amount ofthe compounds and/or the pharmaceutical compositions of the invention.

In another aspect, the invention provides a method of treating a diseaseor disorder associated with upregulated and/or dysregulated macrophagemigration inhibitory factor expression in a subject in need thereof, themethod comprising administering to the subject an effective amount ofthe compound of any of the compounds and/or the pharmaceuticalcompositions of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description of illustrative embodiments of theinvention will be better understood when read in conjunction with theappended drawings. For the purpose of illustrating the invention,certain illustrative embodiments are shown in the drawings. It should beunderstood, however, that the invention is not limited to the precisearrangements and instrumentalities of the embodiments shown in thedrawings.

FIG. 1 is a rendering from an 1.8-Å crystal structure of an analog of 2bound to MIF. Carbon atoms of the inhibitor are colored yellow. Hydrogenbonds are indicated with dashed lines.

FIG. 2 is a rendering from the 2.0-Å crystal structure of 5 bound toMIF. Details as in FIG. 1.

FIG. 3 is a rendering from the 2.3-Å crystal structure of 8a bound toMIF. Details as in FIG. 1.

FIG. 4 is a rendering from the 2.0-Å crystal structure of 8n bound toMIF. Details as in FIG. 1.

FIGS. 5A-5C depict schemes for the synthesis of inhibitors 6ac, 7a, 7b,and 8ax.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention provides novel compounds that, in variousembodiments, act as inhibitors of MIF. In various aspects andembodiments, the invention provides methods of treating diseaseassociated with upregulated and/or dysregulated MIF expression, such asbut not limited to inflammatory diseases or disorder, neurologicaldiseases or disorders, and/or cancer in a subject by administering tothe subject a pharmaceutical composition containing an effective amountof at least one of the compounds of the invention.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methodsand materials are described. As used herein, each of the following termshas the meaning associated with it in this section.

Generally, the nomenclature used herein and the laboratory procedures incell culture, molecular genetics, pharmacology, and organic chemistryare those well-known and commonly employed in the art.

Standard techniques are used for biochemical and/or biologicalmanipulations. The techniques and procedures are generally performedaccording to conventional methods in the art and various generalreferences (e.g., Sambrook and Russell, 2012, Molecular Cloning, ALaboratory Approach, Cold Spring Harbor Press, Cold Spring Harbor, N.Y.,and Ausubel et al., 2002, Current Protocols in Molecular Biology, JohnWiley & Sons, NY), which are provided throughout this document.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

“About” as used herein when referring to a measurable value such as anamount, a temporal duration, and the like, is meant to encompassvariations of ±20% or ±10%, more preferably ±5%, even more preferably±1%, and still more preferably ±0.1% from the specified value, as suchvariations are appropriate to perform the disclosed methods.

As used herein, the terms “analog,” “analogue,” or “derivative” aremeant to refer to a chemical compound or molecule made from a parentcompound or molecule by one or more chemical reactions. As such, ananalog can be a structure having a structure similar to that of thesmall molecules described herein or can be based on a scaffold of asmall molecule described herein, but differing from it in respect tocertain components or structural makeup, which may have a similar oropposite action metabolically.

As used herein, the term “binding” refers to the adherence of moleculesto one another, such as, but not limited to, enzymes or any otherproteins to substrates, antibodies to antigens, DNA strands to theircomplementary strands. Binding occurs because the shape and chemicalnature of parts of the molecule surfaces are complementary. A commonmetaphor is the “lock-and-key” used to describe how enzymes fit aroundtheir substrate.

A “disease” is a state of health of an animal, such as a human subject,wherein the animal cannot maintain homeostasis, and wherein if thedisease is not ameliorated then the animal's health continues todeteriorate. In contrast, a “disorder” in an animal is a state of healthin which the animal is able to maintain homeostasis, but in which theanimal's state of health is less favorable than it would be in theabsence of the disorder. Left untreated, a disorder does not necessarilycause a further decrease in the animal's state of health.

A “disease or disorder associated with high MIF expression” as usedherein, refers to any disease or disorder where high levels of MIFexpression at the level of transcription or translation or high levelsof MIF activity play a role in the pathogenesis or contribute in any wayto the progression or maintenance of the disease. By way of non-limitingexample, a disease or disorder associated with high MIF expression mayinclude bacterial, viral or fungal infection, asthma, arthritis, autismspectrum disorder, schizophrenia, cancer, anemia of chronic disease,malaria, Crohn's disease and lupus.

An “effective amount” of a compound, as used herein, is that amount ofcompound which is sufficient to achieve the intended effect, typically,treatment or prevention of a disease or disorder, when provided to thepatient by a particular method of administration. An appropriateeffective amount in any individual case may be determined by one ofordinary skill in the art using routine experimentation and the materialdisclosed herein.

As used herein, the phrase “a first compound is essentially free of asecond compound” in a composition indicates that the ratio of the secondcompound to the first second compound in the composition is about 10:90,5:95, 4:96, 3:97, 2:98, 1:99, 0.5:99.5, 0.25:99.75, 0.1:99.9,0.05:99.95, 0.025:99.975, 0.01:99.99 or 0:100.

The terms “patient,” “subject,” “individual,” and the like are usedinterchangeably herein, and refer to any animal, or cells thereofwhether in vitro or in situ, amenable to the methods described herein.In certain non-limiting embodiments, the patient, subject or individualis a human.

As used herein, the terms “pharmaceutically acceptable carrier” and“pharmaceutically acceptable excient” are used interchangeably and meana pharmaceutically acceptable material, composition or carrier, such asa liquid or solid filler, stabilizer, dispersing agent, suspendingagent, diluent, excipient, thickening agent, solvent or encapsulatingmaterial, involved in carrying or transporting a compound useful withinthe invention within or to the patient such that it may perform itsintended function. Typically, such constructs are carried or transportedfrom one organ, or portion of the body, to another organ, or portion ofthe body. Each carrier must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation, including thecompound useful within the invention, and not injurious to the patient.Some examples of materials that may serve as pharmaceutically acceptablecarriers include: sugars, such as lactose, glucose and sucrose;starches, such as corn starch and potato starch; cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients,such as cocoa butter and suppository waxes; oils, such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols, such as propylene glycol; polyols, such asglycerin, sorbitol, mannitol and polyethylene glycol; esters, such asethyl oleate and ethyl laurate; agar; buffering agents, such asmagnesium hydroxide and aluminum hydroxide; surface active agents;alginic acid; pyrogen-free water; isotonic saline; Ringer's solution;ethyl alcohol; phosphate buffer solutions; and other non-toxiccompatible substances employed in pharmaceutical formulations. As usedherein, “pharmaceutically acceptable carrier” also includes any and allcoatings, antibacterial and antifungal agents, and absorption delayingagents, and the like that are compatible with the activity of thecompound useful within the invention, and are physiologically acceptableto the patient. Supplementary active compounds may also be incorporatedinto the compositions. The “pharmaceutically acceptable carrier” mayfurther include a pharmaceutically acceptable salt of the compounduseful within the invention. Other additional ingredients that may beincluded in the pharmaceutical compositions used in the practice of theinvention are known in the art and described, for example in Remington'sPharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton,Pa.), which is incorporated herein by reference.

As used herein, the language “pharmaceutically acceptable salt” refersto a salt of the administered compounds prepared from pharmaceuticallyacceptable non-toxic acids, including inorganic acids or bases, organicacids or bases, solvates, hydrates, or clathrates thereof.

By the term “specifically binds,” as used herein, is meant a molecule,such as an antibody, which recognizes and binds to another molecule orfeature, but does not substantially recognize or bind other molecules orfeatures in a sample.

As used herein, the term “alkoxy” employed alone or in combination withother terms means, unless otherwise stated, an alkyl group having thedesignated number of carbon atoms, as defined elsewhere herein,connected to the rest of the molecule via an oxygen atom, such as, forexample, methoxy, ethoxy, 1-propoxy, 2-propoxy (or isopropoxy) and thehigher homologs and isomers. A specific example is (C₁-C₃)alkoxy, suchas, but not limited to, ethoxy and methoxy.

As used herein, the term “alkyl” by itself or as part of anothersubstituent means, unless otherwise stated, a straight or branched chainhydrocarbon having the number of carbon atoms designated (i.e., C₁-C₁₀means one to ten carbon atoms) and includes straight, branched chain, orcyclic substituent groups. Examples include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, andcyclopropylmethyl. A specific embodiment is (C₁-C₆)alkyl, such as, butnot limited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyland cyclopropylmethyl.

As used herein, the term “aromatic” refers to a carbocycle orheterocycle with one or more polyunsaturated rings and having aromaticcharacter, i.e., having (4n+2) delocalized 7E (pi) electrons, where ‘n’is an integer.

As used herein, the term “aryl” employed alone or in combination withother terms means, unless otherwise stated, a carbocyclic aromaticsystem containing one or more rings (typically one, two or three rings)wherein such rings may be attached together in a pendent manner, such asa biphenyl, or may be fused, such as naphthalene. Examples includephenyl, anthracyl and naphthyl. Aryl groups also include, for example,phenyl or naphthyl rings fused with one or more saturated or partiallysaturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl, orindanyl), which can be substituted at one or more carbon atoms of thearomatic and/or saturated or partially saturated rings.

As used herein, the term “aryl-(C₁-C₆)alkyl” refers to a functionalgroup wherein a one to six carbon alkanediyl chain is attached to anaryl group, e.g., —CH₂CH₂-phenyl or —CH₂-phenyl (or benzyl). Specificexamples are aryl-CH₂— and aryl-CH(CH₃)—. The term “substitutedaryl-(C₁-C₆)alkyl” refers to an aryl-(C₁-C₆)alkyl functional group inwhich the aryl group is substituted. A specific example is substitutedaryl(CH₂)—. Similarly, the term “heteroaryl-(C₁-C₆)alkyl” refers to afunctional group wherein a one to three carbon alkanediyl chain isattached to a heteroaryl group, e.g., —CH₂CH₂-pyridyl. A specificexample is heteroaryl-(CH₂)—. The term “substitutedheteroaryl-(C₁-C₆)alkyl” refers to a heteroaryl-(C₁-C₆)alkyl functionalgroup in which the heteroaryl group is substituted. A specific exampleis substituted heteroaryl-(CH₂)—.

As used herein, the term “cycloalkyl” by itself or as part of anothersubstituent refers to, unless otherwise stated, a cyclic chainhydrocarbon having the number of carbon atoms designated (i.e., C₃-C₆refers to a cyclic group comprising a ring group consisting of three tosix carbon atoms) and includes straight, branched chain or cyclicsubstituent groups. Examples of (C₃-C₆)cycloalkyl groups arecyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl ringscan be optionally substituted. Non-limiting examples of cycloalkylgroups include: cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl,cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl,cyclooctanyl, decalinyl, 2,5-dimethylcyclopentyl,3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl,3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, octahydro-1H-indenyl,3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl;bicyclo[6.2.0]decanyl, decahydronaphthalenyl, anddodecahydro-1H-fluorenyl. The term “cycloalkyl” also includes bicyclichydrocarbon rings, non-limiting examples of which include,bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl,1,3-dimethyl[2.2.1] heptan-2-yl, bicyclo[2.2.2]octanyl, andbicyclo[3.3.3]undecanyl.

As used herein, the term “halide” refers to a halogen atom bearing anegative charge. The halide anions are fluoride (F⁻), chloride (Cl⁻),bromide (Br⁻), and iodide (I⁻).

As used herein, the term “halo” or “halogen” alone or as part of anothersubstituent refers to, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom.

As used herein, the term “heteroalkenyl” by itself or in combinationwith another term refers to, unless otherwise stated, a stable straightor branched chain monounsaturated or diunsaturated hydrocarbon groupconsisting of the stated number of carbon atoms and one or twoheteroatoms selected from the group consisting of O, N, and S, andwherein the nitrogen and sulfur atoms may optionally be oxidized and thenitrogen heteroatom may optionally be quaternized. Up to two heteroatomsmay be placed consecutively. Examples include —CH═CH—O—CH₃,—CH═CH—CH₂—OH, —CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, and —CH₂—CH═CH—CH₂—SH.

As used herein, the term “heteroalkyl” by itself or in combination withanother term refers to, unless otherwise stated, a stable straight orbranched chain alkyl group consisting of the stated number of carbonatoms and one or two heteroatoms selected from the group consisting ofO, N, and S, and wherein the nitrogen and sulfur atoms may be optionallyoxidized and the nitrogen heteroatom may be optionally quaternized. Theheteroatom(s) may be placed at any position of the heteroalkyl group,including between the rest of the heteroalkyl group and the fragment towhich it is attached, as well as attached to the most distal carbon atomin the heteroalkyl group. Examples include: —OCH₂CH₂CH₃, —CH₂CH₂CH₂OH,—CH₂CH₂NHCH₃, —CH₂SCH₂CH₃, and —CH₂CH₂S(═O)CH₃. Up to two heteroatomsmay be consecutive, such as, for example, —CH₂NH—OCH₃, or —CH₂CH₂SSCH₃.

As used herein, the term “heteroaryl” or “heteroaromatic” refers to aheterocycle having aromatic character. A polycyclic heteroaryl mayinclude one or more rings that are partially saturated. Examples includetetrahydroquinoline and 2,3-dihydrobenzofuryl.

As used herein, the term “heterocycle” or “heterocyclyl” or“heterocyclic” by itself or as part of another substituent refers to,unless otherwise stated, an unsubstituted or substituted, stable, mono-or multi-cyclic heterocyclic ring system that comprises carbon atoms andat least one heteroatom selected from the group consisting of N, O, andS, and wherein the nitrogen and sulfur heteroatoms may be optionallyoxidized, and the nitrogen atom may be optionally quaternized. Theheterocyclic system may be attached, unless otherwise stated, at anyheteroatom or carbon atom that affords a stable structure. A heterocyclemay be aromatic or non-aromatic in nature. In certain embodiments, theheterocycle is a heteroaryl.

Examples of non-aromatic heterocycles include monocyclic groups such asaziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane,2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane,piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine,morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran,1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane,4,7-dihydro-1,3-dioxepin and hexamethyleneoxide.

Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl(such as, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl,thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl,isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl,tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyland 1,3,4-oxadiazolyl.

Examples of polycyclic heterocycles include indolyl (such as, but notlimited to, 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl,tetrahydroquinolyl, isoquinolyl (such as, but not limited to, 1- and5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl(such as, but not limited to, 2- and 5-quinoxalinyl), quinazolinyl,phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin,dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (such as, but notlimited to, 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl,1,2-benzisoxazolyl, benzothienyl (such as, but not limited to, 3-, 4-,5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (such as, butnot limited to, 2-benzothiazolyl and 5-benzothiazolyl), purinyl,benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl,acridinyl, pyrrolizidinyl, and quinolizidinyl.

The aforementioned listing of heterocyclyl and heteroaryl moieties isintended to be representative and not limiting.

As used herein, the term “substituted” refers to that an atom or groupof atoms has replaced hydrogen as the substituent attached to anothergroup.

As used herein, the term “substituted alkyl,” “substituted cycloalkyl,”“substituted alkenyl” or “substituted alkynyl” refers to alkyl,cycloalkyl, alkenyl or alkynyl, as defined elsewhere herein, substitutedby one, two or three substituents independently selected from the groupconsisting of halogen, —OH, alkoxy, tetrahydro-2-H-pyranyl, —NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, 1-methyl-imidazol-2-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, —C(═O)OH, —C(═O)O(C₁-C₆)alkyl,trifluoromethyl, —C(═O)NH₂, —C(═O)NH(C₁-C₆)alkyl,—C(═O)N((C₁-C₆)alkyl)₂, —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆alkyl)₂, —C(═NH)NH₂, and —NO₂, in certain embodiments containing one ortwo substituents independently selected from halogen, —OH, alkoxy, —NH₂,trifluoromethyl, —N(CH₃)₂, and —C(═O)OH, in certain embodimentsindependently selected from halogen, alkoxy and —OH. Examples ofsubstituted alkyls include, but are not limited to, 2,2-difluoropropyl,2-carboxycyclopentyl and 3-chloropropyl.

For aryl, aryl-(C₁-C₃)alkyl and heterocyclyl groups, the term“substituted” as applied to the rings of these groups refers to anylevel of substitution, namely mono-, di-, tri-, tetra-, orpenta-substitution, where such substitution is permitted. Thesubstituents are independently selected, and substitution may be at anychemically accessible position. In certain embodiments, the substituentsvary in number between one and four. In other embodiments, thesubstituents vary in number between one and three. In yet anotherembodiments, the substituents vary in number between one and two. In yetother embodiments, the substituents are independently selected from thegroup consisting of C₁-C₆ alkyl, —OH, C₁-C₆ alkoxy, halo, amino,acetamido and nitro. As used herein, where a substituent is an alkyl oralkoxy group, the carbon chain may be branched, straight or cyclic.

Unless otherwise noted, when two substituents are taken together to forma ring having a specified number of ring atoms (e.g., two groups takentogether with the nitrogen to which they are attached to form a ringhaving from 3 to 7 ring members), the ring can have carbon atoms andoptionally one or more (e.g., 1 to 3) additional heteroatomsindependently selected from nitrogen, oxygen, or sulfur. The ring can besaturated or partially saturated, and can be optionally substituted.

Whenever a term or either of their prefix roots appear in a name of asubstituent the name is to be interpreted as including those limitationsprovided herein. For example, whenever the term “alkyl” or “aryl” oreither of their prefix roots appear in a name of a substituent (e.g.,arylalkyl, alkylamino) the name is to be interpreted as including thoselimitations given elsewhere herein for “alkyl” and “aryl” respectively.

In certain embodiments, substituents of compounds are disclosed ingroups or in ranges. It is specifically intended that the descriptioninclude each and every individual subcombination of the members of suchgroups and ranges. For example, the term “C₁₋₆ alkyl” is specificallyintended to individually disclose C₁, C₂, C₃, C₄, C₅, C₆, C₁-C₆, C₁-C₅,C₁-C₄, C₁-C₃, C₁-C₂, C₂-C₆, C₂-C₅, C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄,C₄-C₆, C₄-C₅, and C₅-C₆ alkyl.

Ranges: throughout this disclosure, various aspects of the invention canbe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 and so forth, as well as individualnumbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6.This applies regardless of the breadth of the range.

Compounds

In one aspect, the invention provides compounds according to formula (I)or a salt, solvate, stereoisomer (such as, in a non-limiting example, anenantiomer or diastereoisomer, and any mixtures thereof, such as, in anon-limiting example, mixtures in any proportion of enantiomers and/ordiastereoisomers thereof), tautomer and any mixtures thereof, and/orgeometric isomer and any mixtures thereof:

wherein in (I):

Y is selected from the group consisting of a bond, —CH₂—, —O—, —S—,—S(═O)—, —S(═O)₂, and —N(R₂)—;

R₁ is selected from the group consisting of H, C₁-C₆ alkyl, phenyl,naphthyl, tetrahydronaphthyl, phenanthryl, bicyclic heteroaryl (such as,but not limited to, benzofuranyl, benzothiophenyl, and indolyl),1,2-dihydroacenaphthyl, acenaphthyl, adamantyl, (heteroaryl)-phenyl, andbiphenyl;

R₂ is selected from the group consisting of H and C₁-C₆ alkyl;

Z is selected from the group consisting of —COOR, —S(═O)R, —S(═O)₂R, andSO₂NRR;

X is selected from the group consisting of H, C₁-C₃ alkyl, and a halogen(such as, for example, F or Cl);

-   -   wherein the phenyl, naphthyl, tetrahydronaphthyl, phenanthryl,        bicyclic heteroaryl, 1,2-dihydroacenaphthyl, acenaphthyl,        adamantyl, (heteroaryl)-phenyl, or biphenyl is independently        optionally substituted with at least one group independently        selected from the group consisting of halogen, —OH, —C(═O)OR,        C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,        C₃-C₆ cycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkyl, C₃-C₆        halocycloalkoxy, —(CH₂)₁₋₆NRR, —O(CH₂)₁₋₆NRR, —(CH₂)₁₋₆NR(C₁-C₆        acyl), —O(CH₂)₁₋₆NR(C₁-C₆ acyl), —(CH₂)₁₋₆OR, —O(CH₂)₁₋₆OR,        —(CH₂)₁₋₆C(═O)OR, —O(CH₂)₁₋₆C(═O)OR, —(CH₂)₁₋₆OR, —O(CH₂)₁₋₆OR,        —(OCH₂CH₂)₁₋₆NRR, and —(OCH₂CH₂)₁₋₆C(═O)OR;    -   wherein each occurrence of R is independently selected from the        group consisting of H and C₁-C₆ alkyl, or two R groups combine        with the N atom to which they are both bound to form a 3-8        membered heterocyclyl or heteroaryl group (such as, but not        limited to, piperidinyl, morpholinyl, pyrrolidinyl, pyridinyl,        imidazolyl, and the like).

In certain embodiments, if R₁—Y is H, then Z is not —COOH. In certainembodiments, if R₁—Y is H and Z is —COOR, then X is not H. In certainembodiments, if R₁—Y is H and Z is —COOH, then X is not H.

In certain embodiments, the (heteroaryl)-phenyl is selected from thegroup consisting of (pyrimidinyl)-phenyl, (pyridinyl)-phenyl,(thiophenyl)-phenyl, and the like.

In certain embodiments, the compound of formula (I) is a compound offormula (6):

In various embodiments, R₁ is selected from the group consisting ofphenyl and naphthyl. In various embodiments, the compound is selectedfrom the group consisting of:

In certain embodiments, the compound of formula (I) is a compound offormula (7):

In various embodiments, R₁ is selected from the group consisting ofphenyl and naphthyl. In various embodiments, R₂ is methyl. In variousembodiments, the compound is selected from the group consisting of:

In certain embodiments, the compound of formula (I) is a compound offormula (8):

In various embodiments, R₁ is selected from the group consisting ofmethylphenyl, methoxyphenyl, fluorophenyl, ethylnapthyl,cyclopropylnaphthyl, methylbiphenyl, ethoxybiphenyl, andN-morpholinopropoxybiphenyl. In various embodiments, X is fluorine. Invarious embodiments, the compound is selected from the group consistingof:

The compounds of the invention may possess one or more stereocenters,and each stereocenter may exist independently in either the (R) or (S)configuration. In certain embodiments, compounds described herein arepresent in optically active or racemic forms. The compounds describedherein encompass racemic, optically active, regioisomeric andstereoisomeric forms, or combinations thereof that possess thetherapeutically useful properties described herein. Preparation ofoptically active forms is achieved in any suitable manner, including byway of non-limiting example, by resolution of the racemic form withrecrystallization techniques, synthesis from optically active startingmaterials, chiral synthesis, or chromatographic separation using achiral stationary phase. A compound illustrated herein by the racemicformula further represents either of the two enantiomers or mixturesthereof, or in the case where two or more chiral center are present, alldiastereomers or mixtures thereof.

In certain embodiments, the compounds of the invention exist astautomers. All tautomers are included within the scope of the compoundsrecited herein.

Compounds described herein also include isotopically labeled compoundswherein one or more atoms is replaced by an atom having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number usually found in nature.

Examples of isotopes suitable for inclusion in the compounds describedherein include and are not limited to ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F,¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²F, and ³⁵S. In certainembodiments, substitution with heavier isotopes such as deuteriumaffords greater chemical stability. Isotopically labeled compounds areprepared by any suitable method or by processes using an appropriateisotopically labeled reagent in place of the non-labeled reagentotherwise employed.

In certain embodiments, the compounds described herein are labeled byother means, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

In all of the embodiments provided herein, examples of suitable optionalsubstituents are not intended to limit the scope of the claimedinvention. The compounds of the invention may contain any of thesubstituents, or combinations of substituents, provided herein.

In various embodiments, the compounds of the invention may beincorporated into a pharmaceutical composition comprising at least onepharmaceutically acceptable excipient. Dosage, administration andformulation is discussed elsewhere herein.

Salts

The compounds described herein may form salts with acids or bases, andsuch salts are included in the present invention. The term “salts”embraces addition salts of free acids or bases that are useful withinthe methods of the invention. The term “pharmaceutically acceptablesalt” refers to salts that possess toxicity profiles within a range thataffords utility in pharmaceutical applications. In certain embodiments,the salts are pharmaceutically acceptable salts. Pharmaceuticallyunacceptable salts may nonetheless possess properties such as highcrystallinity, which have utility in the practice of the presentinvention, such as for example utility in process of synthesis,purification or formulation of compounds useful within the methods ofthe invention.

Suitable pharmaceutically acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of inorganicacids include sulfate, hydrogen sulfate, hydrochloric, hydrobromic,hydriodic, nitric, carbonic, sulfuric, and phosphoric acids (includinghydrogen phosphate and dihydrogen phosphate). Appropriate organic acidsmay be selected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which include formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (or pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,sulfanilic, 2-hydroxyethanesulfonic, trifluoromethanesulfonic,p-toluenesulfonic, cyclohexylaminosulfonic, stearic, alginic,β-hydroxybutyric, salicylic, galactaric, galacturonic acid,glycerophosphonic acids and saccharin (e.g., saccharinate, saccharate).Salts may be comprised of a fraction of one, one or more than one molarequivalent of acid or base with respect to any compound of theinvention.

Suitable pharmaceutically acceptable base addition salts of compounds ofthe invention include, for example, ammonium salts and metallic saltsincluding alkali metal, alkaline earth metal and transition metal saltssuch as, for example, calcium, magnesium, potassium, sodium and zincsalts. Pharmaceutically acceptable base addition salts also includeorganic salts made from basic amines such as, for example,N,N′-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (or N-methylglucamine) and procaine. All ofthese salts may be prepared from the corresponding compound by reacting,for example, the appropriate acid or base with the compound.

Methods

In one aspect, the invention provides a method of inhibiting MIFactivity in a subject. In certain embodiments, the method comprisesadministering to a subject at least one compound of the invention, or acomposition comprising the same. In other embodiments, the compound isadministered to the subject by any known means of administration, andoptionally in a pharmaceutical composition further comprising at leastone excipient as appropriate to administer the compound to the subject.

In one aspect, the invention provides a method of treating a disease ordisorder associated with upregulated and/or dysregulated MIF expressionin a subject. In certain embodiments, the method comprises administeringto a subject at least one compound of the invention, or a compositioncomprising the same. In other embodiments, the compound is administeredto the subject by any known means of administration, and optionally in apharmaceutical composition further comprising at least one excipient asappropriate to administer the compound to the subject.

In one aspect, the invention provides a method of treating aninflammatory disease, neurological disorders or cancer in a subject. Incertain embodiments, the method comprises administering to a subject atleast one compound of the invention, or a composition comprising thesame. In other embodiments, the compound is administered to the subjectby any known means of administration, and optionally in a pharmaceuticalcomposition further comprising at least one excipient as appropriate toadminister the compound to the subject.

In various embodiments, the subject has or is at risk of developing thedisease or disorder. Diseases associated with upregulated and/ordysregulated MIF expression include, by way of non-limiting example,diseases caused by infection by a protozoan (for example malaria)fungus, bacteria and viruses, including flavivirus, such as West Nile,Dengue, Japanese encephalitis, St Louis encephalitis, or equineencepahalitis viruses; anemia of chronic disease; asthma and autismspectrum disorder (ASD). In various embodiments, the inflammatorydisease is rheumatoid arthritis, Crohn's disease, or inflammatory bowelsyndrome. In various embodiments, the neurological disorder isschizophrenia. In various embodiments, the cancer is colorectal, lung,breast, or prostate.

Administration/Dosage/Formulations

Administration of the compounds and/or compositions of the presentinvention to a patient, preferably a mammal, more preferably a human,may be carried out using known procedures, at dosages and for periods oftime effective to perform the methods contemplated in the invention. Aneffective amount of the compound necessary may vary according to factorssuch as the state of a disease or disorder in the patient; the age, sex,and weight of the patient. One of ordinary skill in the art would beable to study the relevant factors and make the determination regardingthe effective amount of the compound without undue experimentation.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient that is effective to achieve successfultreatment for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

In certain embodiments, the compositions of the invention are formulatedusing one or more pharmaceutically acceptable excipients or carriers. Incertain embodiments, the pharmaceutical compositions of the inventioncomprise an effective amount of a compound of the invention and apharmaceutically acceptable carrier.

The carrier may be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity may be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use ofsurfactants. Prevention of the action of microorganisms may be achievedby various antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it is preferable to include isotonic agents, for example, sugars,sodium chloride, or polyalcohols such as mannitol and sorbitol, in thecomposition. Prolonged absorption of the injectable compositions may bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate or gelatin.

Compounds of the invention for administration may be in the range offrom about 1 μg to about 10,000 mg, about 20 μg to about 9,500 mg, about40 μg to about 9,000 mg, about 75 μg to about 8,500 mg, about 150 μg toabout 7,500 mg, about 200 μg to about 7,000 mg, about 3050 μg to about6,000 mg, about 500 μg to about 5,000 mg, about 750 μg to about 4,000mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg toabout 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80mg to about 500 mg, and any and all whole or partial incrementstherebetween.

In certain embodiments, the dose of a compound of the invention is fromabout 1 mg and about 2,500 mg. In certain embodiments, a dose of acompound of the invention used in compositions described herein is lessthan about 10,000 mg, or less than about 8,000 mg, or less than about6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, orless than about 2,000 mg, or less than about 1,000 mg, or less thanabout 500 mg, or less than about 200 mg, or less than about 50 mg.Similarly, in certain embodiments, a dose of a second compound asdescribed herein is less than about 1,000 mg, or less than about 800 mg,or less than about 600 mg, or less than about 500 mg, or less than about400 mg, or less than about 300 mg, or less than about 200 mg, or lessthan about 100 mg, or less than about 50 mg, or less than about 40 mg,or less than about 30 mg, or less than about 25 mg, or less than about20 mg, or less than about 15 mg, or less than about 10 mg, or less thanabout 5 mg, or less than about 2 mg, or less than about 1 mg, or lessthan about 0.5 mg, and any and all whole or partial increments thereof.

Formulations may be employed in admixtures with conventional excipients,i.e., pharmaceutically acceptable organic or inorganic carriersubstances suitable for oral, parenteral, nasal, intravenous,subcutaneous, enteral, or any other suitable mode of administration,known to the art. The pharmaceutical preparations may be sterilized andif desired mixed with auxiliary agents, e.g., lubricants, preservatives,stabilizers, wetting agents, emulsifiers, salts for influencing osmoticpressure buffers, coloring, flavoring and/or aromatic substances and thelike. They may also be combined where desired with other active agents,e.g., anti-fibrotic agents.

Routes of administration of any of the compositions of the inventioninclude oral, nasal, rectal, intravaginal, parenteral, buccal,sublingual or topical. The compounds for use in the invention may beformulated for administration by any suitable route, such as for oral orparenteral, for example, transdermal, transmucosal (e.g., sublingual,lingual, (trans) buccal, (trans)urethral, vaginal (e.g., trans- andperivaginally), (intra)nasal and (trans)rectal), intravesical,intrapulmonary, intraduodenal, intragastrical, intrathecal,subcutaneous, intramuscular, intradermal, intra-arterial, intravenous,intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets,capsules, caplets, pills, gel caps, troches, dispersions, suspensions,solutions, syrups, granules, beads, transdermal patches, gels, powders,pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs,suppositories, liquid sprays for nasal or oral administration, drypowder or aerosolized formulations for inhalation, compositions andformulations for intravesical administration and the like. It should beunderstood that the formulations and compositions that would be usefulin the present invention are not limited to the particular formulationsand compositions that are described herein.

Parenteral Administration

As used herein, “parenteral administration” of a pharmaceuticalcomposition includes any route of administration characterized byphysical breaching of a tissue of a subject and administration of thepharmaceutical composition through the breach in the tissue. Parenteraladministration thus includes, but is not limited to, administration of apharmaceutical composition by injection of the composition, byapplication of the composition through a surgical incision, byapplication of the composition through a tissue-penetrating non-surgicalwound, and the like. In particular, parenteral administration iscontemplated to include, but is not limited to, subcutaneous,intravenous, intraperitoneal, intramuscular, intrasternal injection, andkidney dialytic infusion techniques.

Additional Administration Forms

Additional dosage forms of this invention include dosage forms asdescribed in U.S. Pat. Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389;5,582,837; and 5,007,790. Additional dosage forms of this invention alsoinclude dosage forms as described in U.S. Patent Applications Nos.2003/0147952; 2003/0104062; 2003/0104053; 2003/0044466; 2003/0039688;and 2002/0051820. Additional dosage forms of this invention also includedosage forms as described in PCT Applications Nos. WO 03/35041; WO03/35040; WO 03/35029; WO 03/35177; WO 03/35039; WO 02/96404; WO02/32416; WO 01/97783; WO 01/56544; WO 01/32217; WO 98/55107; WO98/11879; WO 97/47285; WO 93/18755; and WO 90/11757.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures, embodiments, claims, and examples described herein.Such equivalents are considered to be within the scope of this inventionand covered by the claims appended hereto. For example, it should beunderstood, that modifications in reaction conditions, including but notlimited to reaction times, reaction size/volume, and experimentalreagents, such as solvents, catalysts, pressures, atmosphericconditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents,with art-recognized alternatives and using no more than routineexperimentation, are within the scope of the present application.

It is to be understood that wherever values and ranges are providedherein, all values and ranges encompassed by these values and ranges,are meant to be encompassed within the scope of the present invention.Moreover, all values that fall within these ranges, as well as the upperor lower limits of a range of values, are also contemplated by thepresent application.

The following examples further illustrate aspects of the presentinvention. However, they are in no way a limitation of the teachings ordisclosure of the present invention as set forth herein.

EXPERIMENTAL EXAMPLES

The invention is further described in detail by reference to thefollowing experimental examples. These examples are provided forpurposes of illustration only, and are not intended to be limitingunless otherwise specified. Thus, the invention should in no way beconstrued as being limited to the following examples, but rather, shouldbe construed to encompass any and all variations which become evident asa result of the teaching provided herein.

Materials and Methods

The materials and methods used in the following illustrative examplesare here described. Reagents and solvents were obtained from commercialsuppliers and used without further purification. Compound 5 waspurchased from Sigma Aldrich for use in MIF activity and solubilityassays. Reactions requiring microwave irradiation were performed oneither a BIOTAGE® Initiator Classic or a BIOTAGE® Initiator+. Reactionswere monitored by thin-layer chromatography (TLC) using Merck pre-coatedsilica gel plates (analytical, SiO₂-60, F₂₅₄). TLC plates werevisualized under UV light (254 nm) and/or by staining with a solution ofpotassium permanganate (7.5 g/L), potassium carbonate (50 g/L), andsodium hydroxide (0.63 g/L) in water. Flash column chromatography wasperformed on a COMBIFLASH® Rf+ (Teledyne Isco, Lincoln, Nebr.) witheither Grace REVELERIS™ (silica gel, particle size 40 μm), REDISEP®(silica gel, particle size 40-63 μm), or REDISEP RF GOLD® (silica gel,particle size 20-40 μm) prepacked cartridges. The purity of finalcompounds (>95%) was determined by high performance liquidchromatography (HPLC), which was performed on a Waters Acquity UPLC®column (C₁₈ 1.7 μm, 2.1×50 mm) using a Waters Acquity UPLC® systemequipped with a Waters Acquity UPLC® Photodiode Array (PDA) eλ Detector(detection from 210-700 nm). Chromatography was performed at a flow rateof 0.6 mL/min using mobile phases A (water with 0.1% formic acid) and B(acetonitrile with 0.1% formic acid) for 0.4 minutes at 95% A, then in alinear gradient from 5% to 95% of B for 1.6 minutes, and held at 95% Bfor 1 minute. Nuclear magnetic resonance (NMR) spectra were recorded oneither an Agilent DD₂ 400 NMR, ¹³C NMR, and ¹⁹F NMR recorded at 400,101, and 376 MHz, respectively), an Agilent DD₂ 500 NMR, ¹³C NMR, and¹⁹F NMR recorded at 500, 126, and 470 MHz, respectively), or an AgilentDD₂ 600 CH NMR and ¹³C NMR recorded at 600 and 151 MHz, respectively).All spectra were recorded at room temperature. Chemical shifts arereported in ppm relative to deuterated solvent as an internal standard(δ_(H) CDCl₃ 7.26 ppm; δ_(C) CDCl₃ 77.16 ppm; δ_(H) DMSO-d₆ 2.50 ppm;δ_(C) DMSO-d₆ 39.52 ppm; δ_(H) CD₃OD 4.87 ppm; δ_(C) CD₃OD 49.00 ppm)with the following convention for describing multiplicity: s=singlet,d=doublet, t=triplet, q=quartet, quint=quintet, app=apparent, br=broadsignal, m=multiplet, dd=doublet of doublets, etc. Low resolution massspectrometry (MS) measurements for intermediate compounds were performedusing an Agilent 1290 UHPLC equipped with an Agilent 6120 quadrupoletime-of-flight (TOF) mass spectrometer operated in both positive andnegative electrospray ionization (ESI). High-resolution massspectrometry (HRMS) measurements of assayed compounds were recordedusing a Waters ACQUITY UPLC® coupled to a Waters XEVO® QTOF massspectrometer equipped with a Waters ZSpray™ electrospray ionizationsource.

Recombinant expression and purification of human MIF was carried out aspreviously reported. Crystallization of MIF in complex with 5 and 8g wasachieved by soaking with apo-MIF crystals, while for the complexes of 8aand 8n, co-crystallization was performed via sitting drop vapordiffusion at 20° C. The structures were determined in-house using aRigaku 007 HF+ diffractometer and Saturn 944+ CCD detector at T=100 K.The crystal structures have been deposited in the RSC Protein Data Bankwith IDs 6CBG (5), 6CBF (8a), 6CB5 (8g), and 6CBH (8n).

HPP Tautomerase Assay

Inhibition of the tautomerase activity of MIF was measured using thesubstrate 4-hydroxyphenyl pyruvic acid (HPP) in a procedure largelyadapted from previous reports. A solution of HPP (10 mM) in acetatebuffer (0.5 M ammonium acetate, pH adjusted to 6.0) was prepared andallowed to incubate overnight in the dark at room temperature to allowfor equilibration of the keto and enol forms. Following the incubationperiod, the HPP solution was stored at 4° C. and used for no more than aweek. For K_(i) determination, MIF protein (final concentration: ca. 50nm) and inhibitor (multiple concentrations in DMSO, maintaining a finalDMSO concentration of 1%) were incubated in borate buffer (0.5 M boricacid, pH 6.2) in a U-bottom 96-well plate (Falcon) for 20 minutes. Anegative control (containing water and DMSO in lieu of protein andinhibitor, respectively) and a positive control (containing DMSO in lieuof inhibitor) were also prepared. The reaction began upon the additionof HPP solution (final concentration: 1.0 mM and 2.5 mM). The absorbancewas monitored at 305 nm for the formation of the borateenol complexusing a Tecan INFINITE® F500 plate reader over 175 seconds. Absorbancewas measured three times for each [inhibitor]-[HPP] combination.Calculation of initial velocities and the nonlinear regression analysesfor the enzyme kinetics were performed using the program Prism 6(GraphPad), setting the Michaelis-Menten constant (K_(m)) to 2.4.Reported K_(i) values represent the average value obtained from twoassays performed on different days. (R)-ISO-1 (purchased from Santa CruzBiotechnology) was used as a control.

Solubility Assay

Aqueous solubility values of selected compounds were obtained via theshake-flask method. The solid sample (1-4 mg) was suspended in 1.5-2.0mL Britton-Robinson (BR) buffer (0.04 M acetic acid, 0.04 M phosphoricacid, 0.04 M boric acid, pH 6.5). The mixture, containing excessundissolved compound, was stirred at 30° C. for 48 hours. The saturatedsolution was separated from the precipitate by filtration through a 0.45μm polyethersulfone membrane (VWR International). The filtrate wasdiluted with BR buffer if necessary, then cut with an equal volume ofDMSO. UV-vis absorbance was measured with an Agilent 8453 UV-visibleSpectroscopy System (200-900 nm). Calibration curves were prepared withsample concentrations ranging from 0.24 μg/mL-0.25 mg/mL in 50:50DMSO/BR buffer. Reported solubility results are the average values oftwo shake-flask experiments run in parallel. Piroxicam (purchased fromSigma-Aldrich) was used as a control, using BR buffer at pH 3.73.

Protein Expression and Purification

Recombinant human MIF was expressed and purified according to publishedprotocols. Briefly, for the purification of MIF, E. coli cell pelletswere suspended in lysis buffer (20 mM Tris, pH 7.5; 20 mM sodiumchloride; 10% glycerol; 2 mM magnesium chloride; 1 cOmplete miniprotease inhibitor cocktail tablet per 250 mL of buffer). The solutionwas sonicated and centrifuged at 27,000G for 30 mins. The supernatantwas filtered through a 0.22 μm syringe filter and loaded on a GEHealthcare Hi-Trap SP HP column in sequence with a GE Healthcare Hi-TrapQ SP column equilibrated with a buffer composed of 20 mM NaCl and 20 mMTris, pH 7.5. MIF bound to neither of the columns. To achieve highestpurity, the flow-through was further purified with a GE HealthcareSuperdex 200 column. The purified protein was concentrated with a 10 kDacentrifugal filter unit to 30 mg/mL, flash-frozen in liquid nitrogen,and stored at −80° C.

Crystallization of MIF in Complex with 5, 8a, 8g and 8n

Reservoir buffer for 5, 8a, and 8n: 0.1 M Tris, pH 7; 3% isopropylalcohol; 2.4 M (NH₄)SO₄ Reservoir buffer for 8g: 0.1 M Tris, pH 7; 3%isopropyl alcohol; 2.0 M (NR₄)SO₄ Crystal structures of MIF in complexwith 5 and 8g were prepared by crystal soaking. Apo MIF was crystallizedby sitting drop vapor diffusion. To crystallize MIF, 1.0 μL of protein(20 mg/mL) in a buffer composed of 20 mM NaCl and 20 mM Tris at pH 7.5was added to 1.0 μL of reservoir buffer. Crystal trays were incubated at20° C. for one week. A 100 mM DMSO stock solution of 5 was diluted to 10mM with reservoir buffer, and 0.5 μL of this dilution were added to adrop containing apo MIF crystals. After a 24-hour incubation period,crystals were cryo-protected in reservoir buffer cut with 25% glyceroland flash-frozen in liquid nitrogen. Soaking of 8g was performed bytransferring apo crystals into a 0.5 μL drop of reservoir buffercontaining 5% of a 200 mM DMSO stock of 8g. After incubation for 24hours, crystals were cryo-protected in reservoir buffer cut with 20%glycerol and 5% of a 200 nM DMSO stock solution of 8g. Crystals wereflash-frozen in liquid nitrogen.

Crystal structures of MIF in complex with 8a and 8n were prepared byco-crystallization. A solution of inhibitor (25 mM), DMSO (25% v/v) andMIF (11.25 mg/mL) was prepared and incubated for 1 hour.Co-crystallization was performed by incubating 1.0 μL of this solutionwith 1.0 μL of reservoir buffer for 1 week. Crystals were cryo-protectedin reservoir buffer cut with 25% glycerol and flash-frozen in liquidnitrogen.

Diffraction Data Collection, Processing and Refinement

Diffraction data were collected in-house on a Rigaku 007 HF+X-raydiffractometer equipped with a Cu rotating anode (λ=1.54178 Å) and aSaturn 944+ CCD detector at T=100 K. Data processing was performed withHKL2000. Crystallographic statistics are given in Table 1. Phases of 5,8a and 8n were obtained by molecular replacement with PDB file 3U18using the CCP4i and Phaser programs. Model building was performed inCoot with iterative restrained refinement (XYZ coordinates, occupancies,isotropic B factors) with Refmac5. Restraints for inhibitors 5, 8a and8n were generated with JLigand. Phases of 8g were obtained by molecularreplacement with PDB file 6CB5 using CCP4i and Phaser, and modelbuilding was performed in Coot with iterative restrained refinement (XYZcoordinates, occupancies, isotropic B factors, riding hydrogen atoms)with Phenix. refine. Restraints for inhibitor 8g were created withPhenix. elbow. From all datasets, a randomly chosen subset (5%) of thereflections was excluded from refinement and used for the computation ofR_(free).

TABLE 1 MIF-ligand complex (PDB code) 5 (6CBG) 8a (6CBF) 8g (6CB5) 8n(6CBH) (A) Data collection and processing Space group P2₁2₁2₁ P2₁2₁2₁P2₁2₁2₁ P2₁2₁2₁ Unit cell parameters: a, b, c (Å) 68.3, 68.3, 86.8 68.3,68.3, 83.3 68.3, 69.1, 89.2 68.1, 68.5, 88.7 (B) Diffraction dataResolution range (Å) 53.68-2.00 52.82-2.30 50.00-1.78 54.20-2.00(2.05-2.00) (2.34-2.30) (1.81-1.78) (2.03-2.00) Unique reflections 2473917430 40550 28209 R(l)_(merge) (%) 10.3 (56.3) 8.0 (65.7) 4.0 (11.2)Completeness (%) 97.92 (93.07) 97.0 (95.0) 98.3 (78.7) 98.3 (93.2)Multiplicity 3.1 (2.0) 6.4 (4.8) 6.5 (2.2) 5.8 (3.8) <//σ(/)> 49.2 (5.8)16.2 (2.4) 21.7 (1.3) 39.8 (10.8) (C) Refinement Resolution range (Å)53.68-2.00 52.82-2.30 37.49-1.78 54.20-2.00 Reflections used in24739/2764 14279/1608 38476/2011 25311/1709 refinement (work/free) FinalR value for all 17.2/20.5 23.7/28.2 17.8/21.3 17.7/21.5 reflections(work/free) (%) Protein residues 342 342 342 342 Inhibitor atoms 28 4256 78 Water molecules 194 18 256 317 RMSD, bond lengths (Å) 0.009 0.0090.010 0.008 RMSD, bond angles (°) 1.4 1.5 1.0 1.5 Ramachandranplot^([b]) Ramachandran favored (%) 98.5 97.6 98.2 97.4 Ramachandranallowed (%) 1.5 1.8 1.4 2.6 Ramachandran outliers (%) 0.0 0.6 0.4 0.0Mean B factors (Å2): Protein non-hydrogen atoms 14.9 34.8 21.5 24.3Inhibitor 20.2 38.2 34.6 33.0 Water molecules 26.6 28.9 29.5 35.2 [a]Values in parenthesis refer to the highest resolution shell. [b]Calculated with MolProbity.²⁶

Example 1

The strategy for interference with the binding of MIF to its receptorCD74 is to find tautomerase inhibitors that change the surfacecharacteristics of MIF. Indeed, numerous studies have shown acorrelation between inhibition of the enzymatic and biologicalactivities of MIF by measuring tautomerase activity, and, for example,MIF/CD74 binding, protein phosphorylation in inflamed cells, productionof interleukins, and glucocorticoid overriding ability. Though many MIFtautomerase inhibitors have been discovered through screening ofcompound libraries, lead optimization to give inhibitors with nanomolarpotency has been limited. The most promising compounds from theliterature have been tested in a tautomerase inhibition assay and onlyfew compounds have sub-micromolar K_(i) values. The results wereconfirmed by measurement of K_(d) values in a fluorescence polarizationassay. Exemplary potent compounds are 1 (NVS-2) and 2 with K_(i) valuesof ca. 0.03 μM, which are ca. 1000-fold lower than for well-known MIFinhibitors such as 3 ((R)-ISO-1) and the chromen-4-one 4 (Scheme 1).

A feature, which is addressed here, is that 1-4 and many othernon-covalent MIF tautomerase inhibitors and substrates contain a phenolsubunit, which lodges in the back of the active site and forms hydrogenbonds with the sidechain of Asn97 (FIG. 1). Though there are more than125 approved drugs that contain a phenolic group including, for example,acetaminophen, albuterol, amoxicillin, raloxifene, and doxycycline, theoral bioavailability of phenols is well-known to often be unacceptablylow owing to metabolic glucoronidation and/or sulfation. Thus, aphenol-free series of MIF tautomerase inhibitors with low-nanomolarpotencies was sought.

Success in the past has come from exchange of the phenol for a 6:5 fusedheteroaromatic incorporating a pyrrole or pyrazole that retains thehydrogen-bond donating character of phenol. However, the MIF active siteis too constricted near Asn97 for this approach to be viable; additionof a methyl group ortho to the hydroxyl group for the compound in FIG. 1leads to a ca. 100-fold loss in activity. Instead, interest has focusedon direct replacement of the phenol by a pyrazole. In fact, in theinitial virtual screening study 11 compounds were found to be active inan assay that measured interference of binding between MIF andimmobilized CD74 ectodomain; and, one contained a pyrazole with theexpected hydrogen bonds to Asn97 in the docked structure. This compound,5, gave an IC50 of 15 μM in the binding assay; however, it showed littleactivity in a tautomerase assay using 4-hydroxyphenylpyruvate (HPP) asthe substrate with a maximum of 30% inhibition at 50 μM. Thus, analternative series from the virtual screening and from de novo designwas pursued, which provided the biaryltriazoles including 2. However,interest in 5 was renewed since in another phenol-containing inhibitorseries rapid metabolic glucoronidation and sulfation were observed. Itwas decided to retest 5 in an HPP tautomerase assay using optimizedprotocols. Though the K_(i) for 5 from this assay was only 113 μM, inview of its low molecular weight and possibilities for substitution inthe phenyl ring, therefore structure-based, computer-aided leadoptimization was performed. As detailed here, this has been successfulin providing pyrazole derivatives with ca. 2000-fold greater potency.

In working with 5, it was noted that it had high solubility in polarmedia. This motivated successful pursuit of a crystal structure with MIFin spite of the modest K_(i) (FIG. 2). There are two copies of 5 in eachMIF trimer. The expected hydrogen bonds with Asn97 have average N—O andN—N lengths of 3.0 and 3.1 Å, while Lys32 has hydrogen bonds with thecarboxylate group of 5 (3.0 and 2.7 Å) and the oxygen atom of Ile64 (2.7Å). The NH of Ile64 also forms one with the carboxylate (2.9 Å), and thephenyl ring of 5 is well packed between Prol, Tyr95, and Phe113. Fromthis structure and model building with the BOMB program, substitutionpara to the pyrazolyl group seemed likely to yield beneficialinteractions with Tyr36 and possibly Phe113. Thus, constructs 6-8 werepursued where R₁ was mostly an aryl group.

The syntheses of 6-8 are detailed below. As summarized in Scheme 3, thekey steps started from the commercially available phenyl iodide 9, whichunderwent Pd- or Cu-mediated coupling to yield phenylaryl, arylanilinyl,or biaryl ether derivatives 10-12. Installation of the pyrazole was thenachieved by a Suzuki coupling to yield esters 13-15, which werehydrolyzed under mild conditions to provide the desired carboxylicacids.

The compounds reported here are listed in Table 2 along with the resultsfrom the tautomerase assay. The identity of assayed compounds wasconfirmed by ¹H and ¹³C NMR and high-resolution mass spectrometry; HPLCanalyses established purity as >95%. As in prior studies, the inhibitionconstants K, were determined using HPP as the substrate. Inhibitoryactivity is monitored by measuring formation of the borate complex ofthe enol product at 305 nm using a Tecan Infinite F500 plate reader. Inaddition, the aqueous solubilities of several compounds were measuredwith a shake-flask procedure. Saturated solutions are filtered(polyethersulfone syringe, 0.2 μm pore) and analyzed by UV-visspectroscopy (Agilent 8453).

TABLE 2 Experimental inhibition constants, K_(i) Cmpd R^(1[a]) R² Z XK_(i) (μM) 5 H — — — 113 6a Ph — — — 20.6 6b 1-Np — — — 19.5 6c 2-Np — —— 5.4 7a Ph H — — 12.7 7b 2-Np Me — — 4.2 8a Ph — COOH H 6.8 8b o-MePh —COOH H 4.3 8c m-MePh — COOH H 3.8 8d p-MePh — COOH H 7.0 8e m-FPh — COOHH 1.7 8f p-FPh — COOH H 4.6 8g 2-Np — COOH H 4.3 8h 2-Np — SO₂Me H 6.48i 2-Np — SO₂NH₂ H 5.6 8j 9-Phenanthryl — COOH H 2.3 8k 2-Adamantyl —COOH H 2.6 8l 4-Acen — COOH H 1.1 8m 1-Np — COOH F 0.48 8n 2-Np — COOH F0.51 8o 4-Et-2-Np — COOH F 0.15 8p 5-Et-2-Np — COOH F 0.17 8q 7-Et-2-Np— COOH F 0.14 8r 4-Cp-2-Np — COOH F 0.11 8s 4-Cp,7-Et-2-Np — COOH F0.066 8t p-Bp — COOH F 0.35 8u m-Bp — COOH F 0.13 8v 3,5-diMe-m-Bp —COOH F 0.24 8w 4-OEt-m-Bp — COOH F 0.075 8x 4-MrPrO-m-Bp — COOH F 0.067[a] Np = naphthyl; Acen = 1,2-dihydroacenaphthyl; Cp = cyclopropyl; Bp =biphenyl; MrPrO = N-morpholinylpropoxy

Further experimental data are provided in Table 3:

TABLE 3 Experimental inhibition constants, K_(i) HPP No. Z R₁-Y- X Ki 9aCOOMe H 9b SO₂Me H 9c SO₂NH₂ H 9d SO₂NHMe H 9e COOH Me 60 9f COOH3-ClPhO- 20 9g COOH 4-ClPhO- 8.4 9h COOH 4-MeOPhO- 2.3 9i COOH 3-MeOPhO-2.5 9j COOH 4-NH₂CH₂PhO- 9k COOH 3-NH₂CH₂PhO- 9l COOH pMeCONHCH₂CH₂PhO-11 9m COOH 7-benzofuranyl-O- 3.7 9n COOH m-COOHPhO- 9.4 90 COOH5-benzofuranyl-O- 3.8 9p COOH 6-benzofuranyl-O- 1.5 9q COOH4-acenaphthylenyl-O- 1.5 9r COOH Ph-S(=O)- 13 9s COOH 6-benzofuranyl-O-fluoro 0.57 9t COOH m-FPh-O- fluoro 2.1 9u COOH 7-Me-2-Np-O- 1.9 9v COOH1,2-dihydro-4-acenaphthyl-O- fluoro 0.10 9w COOH m-CF₃-PhO- fluoro 0.719x COOH 7-cPr-2-Np-O- fluoro 0.15 9y COOH 2-tetrahydroNp-O- fluoro 0.269z COOH 5-cPr-2-Np-O- fluoro 0.11 9aa COOH 2-pyrimidinyl-3-Ph-O- fluoro0.23 9bb COOH 4-morpholinyl-CH₂CH₂-3-biphenyl-O fluoro 0.33 9cc COOH2-NpO- methyl 15

Consistent with the modeling, addition of an aryl group in 6 did providea significant boost over 5, bringing the K_(i) values down to ca. 20 μMfor a phenyl or 1-naphthyl group and to 5 μM for 2-naphthyl (6c). Theanalogous anilinyl and phenoxy compounds, 7a and 8a, were prepared, andthe greater activity for the complex of 8a with MIF was also obtained(FIG. 3), which does show aryl-aryl contacts between the phenoxy phenylgroup and both Tyr36 and Phe113. A basic SAR (structure-activityrelationship) study was then carried out with 8b-8f, which revealed asmall activity range for addition of a methyl or fluoro substituent,with para-substitution the least favored. Consistent with this guidance,the 2-naphthyl analog 8g was found to show good activity at 4.3 μM; theBOMB modeling indicated increased contact with Phe113 projecting to theright in FIG. 3. Modeling further indicated that still largerhydrophobic groups could be accommodated in this region at the entranceof the MIF active site. This was borne out by K, values of 1-3 μMobtained for phenanthryl, adamantyl, and acenaphthyl analogs, 8j-8l(Scheme 4). However, the project seemed stalled at this point withoutreaching the desired low-nanomolar range and with increasing concernsabout solubility.

For the biaryltriazoles series, it was recalled that placement of afluorine adjacent to the hydroxyl group in compounds like 2 provided aca. 3-fold increase in activity. The effect was attributed to enhancingthe acidity of the phenol, which increases the strength of the hydrogenbond with Asn97, and also to hydrophobic contact of the fluorine withthe side chain of Met 101 (FIG. 1). For the pyrazoles, the enhancedhydrogen bonding could be envisioned for a fluorine at the 3-position;however, the fluorine would project more towards the side chain of Ile64rather than Met101 with uncertain outcome (FIG. 2). Still, a potentialadditional benefit might arise from the influence of the fluorine on thetautomeric equilibrium for the pyrazole. Reliable quantum mechanicalcalculations (MP2/6-311++G**) show that the N1-H tautomer is favored by3.6 kcal/mol over the N2-H tautomer with a fluorine in the 3-position(Scheme 5).^([19]) From the present crystal structures the hydrogenbonds are expected to be more linear for the N1-H tautomer as implied bythe alignment of the side-chain oxygen atom of Asn97 and N1 in FIGS. 2and 3.

Preparation of the fluorinated pyrazole for the Suzuki coupling inScheme 3 proved difficult. Multiple routes were attempted, but successwas only achieved using a SEM [2-(trimethylsilyl)ethoxymethyl]protecting group; the yield was still low, but sufficient to proceed(Scheme 6).

The effort was highly fruitful yielding a nearly 10-fold increase inpotency in progressing from the parent 2-naphthyl inhibitor 8g (4.3 μM)to its fluorinated analog 8n (0.51 μM). It was also possible to obtain acrystal structure for this compound in complex with MIF at 2.0-Åresolution (FIG. 4). The structure confirmed the positioning of thefluorine between the sidechains of Ile64 and Met101. There is one copyof the inhibitor in each MIF trimer in this case; the N—O and N—Nhydrogen bond lengths with Asn97 are 2.87 and 3.12 Å. There are alsoclose-packed Though the exact positioning of the naphthyl group may beinfluenced by crystal packing, the structure and BOMB modeling indicatedthat additional gains in activity could arise from alkyl-substitution atthe 4-, and 5-positions of the naphthyl group to achieve further contactwith Phe113 or at the 7-position for contact with Ile64. This was shownto be correct with the ethyl analogs 8o, 8p, and 8q, which each provideda 3-fold lowering of the K_(i) relative to 8n. Addition of a cyclopropylgroup at the 4-position also appeared promising for interaction with thefront edge of Phe113; this was realized with 8r bringing the K_(i) to0.11 μM. Combining this with the 7-ethyl substitution provided the verypotent 8s with a K, of 0.066 μM. From the structures for 8a and 8n(FIGS. 3 and 4) and modeling, it was also clear that it should bepossible to expand to a biphenyl at either the para or meta position of8a. Thus, 8t and 8u were synthesized and provided significantly lowerK_(i) values (0.35 and 0.13 μM) than the unsubstituted naphthyl analogs,8m and 8n. Substantial activity gains could be expected by judicioussubstitution for the biphenyls; however, only a few derivatives wereprepared with 8w and 8x (Scheme 4) demonstrating ca. 0.07 μM potency andthat large groups can be extended into the solvent from the terminal4-position.

Two additional items are worth noting. First, the results for 8g, 8h,and 8i show that the carboxylic acid group may be replaced by amethylsulfone or sulfonamide with little impact on potency. This isrelevant if one wished to explore these compounds as potentialneurological agents, since sulfones are expected to exhibit betterpenetration of the blood-brain barrier than carboxylic acids orsulfonamides. Secondly, it is always important to monitor aqueoussolubilities for compounds of interest for oral administration. Mostoral drugs are observed to have aqueous solubilities of 4 to 4000 μg/mL,which translates to 10 μM to 10 mM for a drug with a molecular weight of400. ^([21]) The solubilities of several of the present compounds weremeasured in Britton-Robinson buffer at pH 6.5. As noted, the solubilityof the starting compound 5 is very high (927±88 μg/mL). The solubilityof the parent 2-naphthyl analog 8g is also high (739±32 μg/mL); it isaffected little by addition of the fluorine in 8n (681±59 μg/mL), whileswitch to the sulfonamide 8i yields a significant reduction (55.2±4.8μg/mL). Given these results, it was surprising to find in the biphenylseries that the solubility of 8w is only 1.7±0.7 μg/mL. However, this isreadily remedied by attachment of solvent-exposed, solubilizing groupsas in 8x (34.6±4.8 μg/mL, or 67 μM).

Synthesis of 10a-c Methyl 4-bromo-[1,1′-biphenyl]-2-carboxylate (10a)

Methyl 5-bromo-2-iodobenzoate (500 mg, 1.47 mmol), phenylboronic acid(197 mg, 1.61 mmol), Pd(OAc)₂ (16.5 mg, 0.0733 mmol), andtriphenylphosphine (38.5 mg, 0.147 mmol) were dissolved in a solution of2M aqueous Na₂SO₄ (2.5 mL) and acetone (6 mL). The mixture was degassedwith N₂ for 7 minutes then heated at reflux for 18 hours. The reactionmixture was diluted with EtOAc (100 mL) and washed with brine (100 mL).The organic phase was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. Purification by flash column chromatography (hexanesto 90:10 hexanes/EtOAc) afforded 10a as a clear oil (326 mg, 76% yield).R_(f)=0.47 (hexanes/EtOAc 90:10 v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.99 (d,J=2.1 Hz, 1H), 7.67 (dd; J=8.2, 2.1 Hz; 1H), 7.45-7.38 (m, 3H),7.32-7.27 (m, 3H), 3.67 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 167.8,141.5, 140.2, 134.3, 132.8, 132.5, 132.4, 132.4, 128.3, 127.7, 121.2,52.4. MS (ESI⁺) calcd for [C₁₄H₁₂BrO₂]⁺ [M+H]⁺, 291.0; found 290.9.

Methyl 5-bromo-2-(naphthalen-1-yl)benzoate (10b)

Phenyl bromide 10b was prepared according to the procedure for 10a usingmethyl 5-bromo-2-iodobenzoate (500 mg, 1.47 mmol), naphthalene-1-boronicacid (252 mg, 1.47 mmol), Pd(OAc)₂ (16.5 mg, 0.0733 mmol), andtriphenylphosphine (38.5 mg, 0.147 mmol) in 2M aqueous Na₂SO₄ (2.5 mL)and acetone (6 mL). Purification by flash column chromatography (hexanesto 85:15 hexanes/EtOAc) afforded 10b as a white solid (442 mg, 88%yield). R_(f)=0.50 (hexanes/EtOAc 90:10 v/v). ¹H NMR (400 MHz, CDCl₃) δ8.18 (d, J=2.0 Hz, 1H), 7.88 (app t, J=8.7 Hz, 2H), 7.74 (dd, J=8.2, 2.1Hz, 1H), 7.54-7.43 (m, 3H), 7.41-7.35 (m, 1H), 7.31-7.27 (m, 2H), 3.39(s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 166.6, 140.4, 138.5, 134.7, 133.6,133.4, 133.2, 133.1, 131.9, 128.4, 128.1, 126.3, 126.1, 125.9, 125.3,125.2, 121.6, 52.2. MS (ESI⁺) calculated for [C₁₈H₁₃BrNaO₂]⁺ [M+Na]⁺,363.0; found 363.0.

Methyl 5-bromo-2-(naphthalen-2-yl)benzoate (10c)

Phenyl bromide 10c was prepared according to the procedure for 10a usingmethyl 5-bromo-2-iodobenzoate (500 mg, 1.47 mmol), 2-naphthylboronicacid (252 mg, 1.47 mmol), Pd(OAc)₂ (16.5 mg, 0.0733 mmol), andtriphenylphosphine (38.5 mg, 0.147 mmol) in 2M aqueous Na₂SO₄ (2.5 mL)and acetone (6 mL). Purification by flash column chromatography (hexanesto 85:15 hexanes/EtOAc) afforded 10c as a white solid (391 mg, 78%yield). R_(f)=0.42 (hexanes/EtOAc 90:10 v/v). ¹H NMR (400 MHz, CDCl₃) δ8.03 (d, J=2.0 Hz, 1H), 7.90-7.83 (m, 3H), 7.77 (s, 1H), 7.69 (dd,J=8.2, 2.1 Hz, 1H), 7.55-7.48 (m, 2H), 7.39 (dd, J=8.5, 1.7 Hz, 1H),7.35 (d, J=8.2 Hz, 1H), 3.62 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 167.8,141.5, 137.8, 134.5, 133.3, 132.9, 132.8, 132.7, 132.6, 128.2, 127.9,127.7, 127.0, 126.8, 126.5, 126.4, 121.4, 52.4. MS (ESI⁺) calculated for[C₁₈H₁₄BrO₂]⁺ [M+H]⁺, 341.0; found 341.0.

Synthesis of 11a and 11b Methyl 5-bromo-2-(phenylamino)benzoate (11a)

A mixture of methyl 5-bromo-2-iodobenzoate (300 mg, 0.880 mmol), aniline(115 mg, 1.23 mmol), Pd₂(dba)₃ (8.1 mg, 0.0088 mmol), Xantphos (10.2 mg,0.0176 mmol), and Cs₂CO₃ (401 mg, 1.23 mmol) suspended in anhydrousdioxane (1.5 mL) was heated at 100° C. under N₂ atmosphere for 16 hours.The reaction mixture was diluted with EtOAc (100 mL) and washed withbrine (100 mL). The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. Purification by flash columnchromatography (hexanes to 80:20 hexanes/EtOAc) afforded 11a as a yellowoil (234 mg, 87% yield). R_(f)=0.63 (hexanes/EtOAc 90:10 v/v). ¹H NMR(400 MHz, CDCl₃) δ 9.42 (br s, 1H), 8.07 (d, J=2.3 Hz, 1H), 7.39-7.32(m, 3H), 7.22 (d, J=7.8 Hz, 2H), 7.12 (t, J=8.4 Hz, 2H), 3.91 (s, 3H).¹³C NMR (101 MHz, CDCl₃) δ 168.0, 147.2, 140.3, 136.9, 134.0, 129.6,124.3, 123.0, 115.9, 113.3, 108.4, 52.2. MS (ESI⁺) calculated for[C₁₄H₁₃BrNO₂]⁺ [M+H]⁺, 306.0; found 306.1.

Methyl 5-bromo-2-(naphthalen-2-ylamino)benzoate (11b′)

Amine 11b′ was prepared according to the procedure for 11a using methyl5-bromo-2-iodobenzoate (667 mg, 1.96 mmol), 2-naphthylamine (200 mg,1.40 mmol), Pd₂(dba)₃ (12.8 mg, 0.0140 mmol), Xantphos (16.2 mg, 0.0279mmol), and Cs₂CO₃ (637 mg, 1.96 mmol) in anhydrous dioxane (2.5 mL).Purification by flash column chromatography (hexanes to 80:20hexanes/EtOAc) afforded 11b′ as a yellow oil (484 mg, 97% yield).R_(f)=0.29 (hexanes/EtOAc 90:10 v/v). ¹H NMR (600 MHz, CDCl₃) δ 9.60 (s,1H), 8.10 (app t, J=1.8 Hz, 1H), 7.84-7.79 (m, 2H), 7.74 (d, J=8.1 Hz,1H), 7.64 (s, 1H), 7.47 (app t, J=7.5 Hz, 1H), 7.42 (d, J=7.5 Hz, 1H),7.41-7.38 (m, 1H), 7.36-7.33 (m, 1H), 7.23 (d, J=9.0 Hz, 1H), 3.93 (s,3H). ¹³C NMR (151 MHz, CDCl₃) δ 168.0, 147.0, 137.9, 137.0, 134.3,134.0, 130.8, 129.5, 127.8, 127.2, 126.7, 125.1, 123.1, 118.7, 116.2,113.6, 108.7, 52.2. MS (ESI⁺) calculated for [C₁₈H₁₅BrNO₂]⁺ [M+H]⁺,356.0; found 356.0.

Methyl 5-bromo-2-(methyl(naphthalen-2-yl)amino)benzoate (11b)

To a suspension of NaH (60% dispersion in mineral oil, 29.7 mg, 0.737mmol) in anhydrous DMF (1.5 mL) at 0° C. was added amine 11b′ (dissolvedin 1.5 mL DMF, 150 mg, 0.421 mmol) dropwise. After 15 minutes, methyliodide (0.10 mL, 1.7 mmol) was added, and the contents were stirred at80° C. for 3 hours. The reaction mixture was diluted with EtOAc (90 mL)and washed with brine (90 mL). The organic phase was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. Purificationby flash column chromatography (hexanes to 85:15 hexanes/EtOAc) afforded11b as a yellow oil (37.6 mg, 24% yield). R_(f)=0.43 (hexanes/EtOAc90:10 v/v). ^(1H) NMR (600 MHz, CDCl₃) δ 7.95 (d, J=2.4 Hz, 1H),7.69-7.62 (m, 3H), 7.58 (d, J=9.0 Hz, 1H), 7.37 (app t, J=7.5 Hz, 1H),7.24 (app t, J=7.4 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 7.01 (d, J=2.2 Hz,1H), 6.85 (dd, J=9.0, 2.4 Hz, 1H), 3.53 (s, 3H), 3.37 (s, 3H). ¹³C NMR(151 MHz, CDCl₃) δ 166.1, 147.4, 146.6, 136.3, 134.8, 134.5, 130.7,130.6, 128.7, 128.0, 127.6, 126.6, 126.5, 123.0, 118.2, 118.0, 109.1,52.5, 40.9. MS (ESI⁺) calculated for [C₁₉H₁₇BrNO₂]⁺ [M+H]⁺, 370.0; found370.0.

Synthesis of 12a-g, 12j, and 12l-x Methyl 5-bromo-2-phenoxybenzoate(12a)

This procedure was adapted from Marcoux et al.¹ Methyl5-bromo-2-iodobenzoate (750 mg, 2.20 mmol), phenol (104 mg, 1.10 mmol),Cs₂CO₃ (717 mg, 2.20 mmol), (CuOTf)₂.PhH (27.7 mg, 0.0550 mmol),1-naphthoic acid (284 mg, 1.65 mmol), and 4 Å molecular sieves (625 mg)were suspended in anhydrous toluene (2.5 mL) in a vial. The vial wassealed, and the mixture was degassed with N₂ for 7 minutes and heated at110° C. for 18 hours. The reaction mixture was filtered through a pad ofcelite, and the filtrate was diluted with EtOAc (100 mL) and washed withbrine (100 mL). The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. Purification by flash columnchromatography (hexanes to 85:15 hexanes/EtOAc) afforded 12a as a yellowoil (300 mg, 89% yield). R_(f)=0.46 (hexanes/EtOAc 90:10 v/v). NMR (400MHz, CDCl₃) δ 8.03 (d, J=2.3 Hz, 1H), 7.54 (dd, J=8.8, 2.4 Hz, 1H), 7.34(t, J=7.5 Hz, 2H), 7.11 (t, J=7.4 Hz, 1H), 6.96 (d, J=8.5 Hz, 2H), 6.85(d, J=8.8 Hz, 1H), 3.82 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 165.0,157.2, 155.7, 136.5, 134.6, 130.0, 124.7, 123.8, 122.4, 118.5, 115.9,52.6. MS (ESI⁺) calculated for [C₁₄H₁₂BrO₃]⁺ [M+H]⁺, 307.0; found 307.0.

Methyl 5-bromo-2-(o-tolyloxy)benzoate (12b)

Phenyl bromide 12b was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (600 mg, 1.76 mmol), o-cresol (95.2 mg,0.880 mmol), Cs₂CO₃ (573 mg, 1.76 mmol), (CuOTf)₂.PhH (22.1 mg, 0.0440mmol), 1-naphthoic acid (277 mg, 1.32 mmol), and 4 Å molecular sieves(500 mg) in anhydrous toluene (2.5 mL). Purification by flash columnchromatography (hexanes to 80:20 hexanes/EtOAc) afforded 12b as a paleyellow solid (130 mg, 46% yield). R_(f)=0.34 (hexanes/EtOAc 95:5 v/v).¹H NMR (600 MHz, CDCl₃) δ 8.01 (d, J=2.5 Hz, 1H), 7.47 (dd, J=8.8, 2.5Hz, 1H), 7.27-7.24 (m, 1H), 7.16 (app t, J=7.5 Hz, 1H), 7.08 (app t,J=7.4 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 3.86 (s,3H), 2.24 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 165.2, 156.3, 154.3,136.3, 134.6, 131.7, 129.8, 127.4, 124.6, 123.4, 120.0, 119.2, 114.7,52.5, 16.2. MS (ESI⁺) calculated for [C₁₅H₁₄BrO₃]⁺ [M+H]⁺, 321.0; found321.1.

Methyl 5-bromo-2-(m-tolyloxy)benzoate (12c)

Phenyl bromide 12c was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (600 mg, 1.76 mmol), m-cresol (95.2 mg,0.880 mmol), Cs₂CO₃ (573 mg, 1.76 mmol), (CuOTf)_(z)PhH (22.1 mg, 0.0440mmol), 1-naphthoic acid (227 mg, 1.32 mmol), and 4 Å molecular sieves(500 mg) in anhydrous toluene (2.5 mL). Purification by flash columnchromatography (hexanes to 90:10 hexanes/EtOAc) afforded 12c as a clearoil (199 mg, 70% yield). R_(f)=0.54 (hexanes/EtOAc 90:10 v/v). ¹H NMR(400 MHz, CDCl₃) δ 8.02 (d, J=2.5 Hz, 1H), 7.53 (dd, J=8.8, 2.5 Hz, 1H),7.21 (app t, J=7.8 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 6.84 (d, J=8.8 Hz,1H), 6.81-6.73 (m, 2H), 3.83 (s, 3H), 2.33 (s, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 165.0, 157.1, 155.9, 140.3, 136.4, 134.5, 129.7, 124.6, 124.6,122.3, 119.3, 115.7, 115.6, 52.6, 21.5. MS (ESI⁺) calculated for[C₁₅H₁₄BrO₃]⁺ [M+H]⁺, 321.0; found 321.1.

Methyl 5-bromo-2-(p-tolyloxy)benzoate (12d)

Phenyl bromide 12d was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (600 mg, 1.76 mmol), p-cresol (95.2 mg,0.880 mmol), Cs₂CO₃ (573 mg, 1.76 mmol), (CuOTf)_(z)PhH (22.1 mg, 0.0440mmol), 1-naphthoic acid (227 mg, 1.32 mmol), and 4 Å molecular sieves(500 mg) in anhydrous toluene (2.5 mL). Purification by flash columnchromatography (hexanes to 90:10 hexanes/EtOAc) afforded 12d as a whitesolid (224 mg, 79% yield). R_(f)=0.49 (hexanes/EtOAc 90:10 v/v). ¹H NMR(400 MHz, CDCl₃) δ 8.01 (d, J=2.5 Hz, 1H), 7.50 (dd, J=8.8, 2.5 Hz, 1H),7.14 (d, J=8.3 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 6.80 (d, J=8.8 Hz, 1H),3.84 (s, 3H), 2.33 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 165.1, 156.3,154.7, 136.3, 134.5, 133.5, 130.5, 124.3, 121.7, 118.8, 115.3, 52.6,20.8. MS (ESI⁺) calculated for [C₁₅H₁₄BrO₃]⁺ [M+H]⁺, 321.0; found 321.1.

Methyl 5-bromo-2-(3-fluorophenoxy)benzoate (12e)

Phenyl bromide 12e was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (600 mg, 1.76 mmol), 3-fluorophenol (98.6mg, 0.880 mmol), Cs₂CO₃ (573 mg, 1.76 mmol), (CuOTf)_(z)PhH (22.1 mg,0.0440 mmol), 1-naphthoic acid (227 mg, 1.32 mmol), and 4 Å molecularsieves (500 mg) in anhydrous toluene (2.5 mL). Purification by flashcolumn chromatography (hexanes to 95:5 hexanes/EtOAc) afforded 12e as aclear oil (91.0 mg, 32% yield). R_(f)=0.23 (hexanes/EtOAc 95:5 v/v). ¹HNMR (400 MHz, CDCl₃) δ 8.06 (d, J=2.5 Hz, 1H), 7.60 (dd, J=8.7, 2.5 Hz,1H), 7.31-7.23 (m, 1H), 6.93 (d, J=8.7 Hz, 1H), 6.83-6.77 (m, 1H), 6.71(dd, J=8.3, 1.6 Hz, 1H), 6.65 (app dt, J=10.1, 2.1 Hz, 1H), 3.81 (s,3H). ¹³C NMR (101 MHz, CDCl₃) δ 164.6, 163.7 (d, J=246.9 Hz), 158.8 (d,J=10.5 Hz), 154.5, 136.7, 134.9, 130.7 (d, J=9.7 Hz), 125.2, 123.4,117.1, 113.4 (d, J=3.1 Hz), 110.3 (d, J=21.2 Hz), 105.7 (d, J=25.0 Hz),52.6. MS (ESI⁺) calculated for [C₁₄H₁₁BrFO₃]⁺ [M+H]⁺, 325.0; found325.0.

Methyl 5-bromo-2-(4-fluorophenoxy)benzoate (12f)

Phenyl bromide 12f was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (600 mg, 1.76 mmol), 4-fluorophenol (98.6mg, 0.880 mmol), Cs₂CO₃ (573 mg, 1.76 mmol), (CuOTf)_(z)PhH (22.1 mg,0.0440 mmol), 1-naphthoic acid (227 mg, 1.32 mmol), and 4 Å molecularsieves (500 mg) in anhydrous toluene (2.5 mL). Purification by flashcolumn chromatography (hexanes to 95:5 hexanes/EtOAc) afforded 12f as ayellow oil (186 mg, 65% yield). R_(f)=0.29 (hexanes/EtOAc 95:5 v/v). ¹HNMR (400 MHz, CDCl₃) δ 8.02 (d, J=2.0 Hz, 1H), 7.53 (dd, J=8.8, 2.2 Hz,1H), 7.03 (t, J=8.5 Hz, 2H), 6.97-6.90 (m, 2H), 6.80 (d, J=8.8 Hz, 1H),3.84 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 164.8, 159.1 (d, J=242.3 Hz),156.0, 152.9 (d, J=2.6 Hz), 136.5, 134.7, 124.5, 121.7, 120.1 (d, J=8.3Hz), 116.6 (d, J=23.5 Hz), 115.9, 52.6. MS (ESI⁺) calculated for[C₁₄H₁₁BrFO₃]⁺ [M+H]⁺, 325.0; found 325.0.

Methyl 5-bromo-2-(naphthalen-2-yloxy)benzoate (12g)

Phenyl bromide 12g was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (750 mg, 2.20 mmol), 2-naphthol (159 mg,1.10 mmol), Cs₂CO₃ (717 mg, 2.20 mmol), (CuOTf)₂.PhH (27.7 mg, 0.0550mmol), 1-naphthoic acid (284 mg, 1.65 mmol), and 4 Å molecular sieves(625 mg) in anhydrous toluene (2.5 mL). Purification by flash columnchromatography (hexanes to 85:15 hexanes/EtOAc) afforded 12g as a lemonyellow oil (86.9 mg, 22% yield). R_(f)=0.42 (hexanes/EtOAc 90:10 v/v).¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J=2.4 Hz, 1H), 7.87-7.80 (m, 2H),7.69 (d, J=8.0 Hz, 1H), 7.57 (dd, J=8.8, 2.5 Hz, 1H), 7.49-7.39 (m, 2H),7.28-7.23 (m, 1H), 7.22 (s, 1H), 6.92 (d, J=8.8 Hz, 1H), 3.81 (s, 3H).¹³C NMR (101 MHz, CDCl₃) δ 164.9, 155.5, 155.1, 136.6, 134.8, 134.3,130.4, 130.2, 127.9, 127.3, 126.8, 125.1, 124.8, 122.8, 119.5, 116.2,113.6, 52.6. MS (ESI⁺) calculated for [C₁₈H₁₄BrO₃]⁺ [M+H]⁺, 357.0; found357.1.

Methyl 5-bromo-2-(phenanthren-9-yloxy)benzoate (12j)

Phenyl bromide 12j was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (600 mg, 1.76 mmol), 9-phenanthrol (171mg, 0.880 mmol), Cs₂CO₃ (573 mg, 1.76 mmol), (CuOTf)_(z)PhH (22.1 mg,0.0440 mmol), 1-naphthoic acid (227 mg, 1.32 mmol), and 4 Å molecularsieves (500 mg) in anhydrous toluene (2.5 mL). Purification by flashcolumn chromatography (hexanes to 90:10 hexanes/EtOAc) afforded 12j as ayellow solid (29.7 mg, 8% yield). R_(f)=0.44 (hexanes/EtOAc 90:10 v/v).¹H NMR (600 MHz, CDCl₃) δ 8.72 (d, J=8.3 Hz, 1H), 8.65 (d, J=8.2 Hz,1H), 8.36 (d, J=8.1 Hz, 1H), 8.15 (s, 1H), 7.74 (app t, J=7.6 Hz, 1H),7.69 (d, J=7.8 Hz, 1H), 7.66 (app t, J=7.6 Hz, 1H), 7.61-7.52 (m, 3H),6.99 (s, 1H), 6.95 (d, J=8.7 Hz, 1H), 3.72 (s, 3H). ¹³C NMR (151 MHz,CDCl₃) δ 165.0, 155.6, 151.8, 136.6, 134.9, 132.1, 131.9, 128.0, 127.9,127.7, 127.2, 127.1, 126.5, 125.8, 124.7, 122.9, 122.8, 122.7, 122.7,116.3, 110.9, 52.6. MS (ESI⁺) calculated for [C₂₂H₁₆BrO₃]⁺ [M+H]⁺,407.0; found 407.0.

Methyl 5-bromo-2-((1,2-dihydroacenaphthylen-4-yl)oxy)benzoate (12l)

Phenyl bromide 12l was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (1.86 g, 5.45 mmol), alcohol 28 (619 mg,3.63 mmol), Cs₂CO₃ (2.37 g, 7.27 mmol), (CuOTf)₂.PhH (91.5 mg, 0.182mmol), 1-naphthoic acid (939 mg, 5.45 mmol), and 4 Å molecular sieves(1.00 g) in anhydrous toluene (10 mL). Purification by flash columnchromatography (hexanes to 90:10 hexanes/EtOAc) afforded 121 as anolive-colored solid (180 mg, 13% yield). R_(f)=0.46 (hexanes/EtOAc 90:10v/v). ¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, J=2.5 Hz, 1H), 7.54 (dd, J=8.8,2.6 Hz, 1H), 7.46-7.40 (m, 2H), 7.22 (d, J=6.0 Hz, 1H), 7.03-7.00 (m,2H), 6.89 (d, J=8.8 Hz, 1H), 3.83 (s, 3H), 3.45-3.40 (m, 2H), 3.40-3.35(m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 165.0, 157.5, 156.2, 148.8, 145.9,136.5, 134.6, 131.8, 128.9, 125.0, 124.6, 122.5, 121.8, 118.6, 115.8,113.3, 109.4, 52.6, 30.8, 30.4. MS (ESI⁺) calculated for [C₂₀H₁₆BrO₃]⁺[M+H]⁺, 383.1; found 383.1.

Methyl 5-bromo-2-(naphthalen-1-yloxy)benzoate (12m)

Phenyl bromide 12m was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (710 mg, 2.08 mmol), 1-naphthol (250 mg,1.73 mmol), Cs₂CO₃ (1.13 g, 3.47 mmol), (CuOTf)_(z)PhH (65.5 mg, 0.130mmol), 1-naphthoic acid (448 mg, 2.60 mmol), and 4 Å molecular sieves(1.00 g) in anhydrous toluene (5 mL). Purification by flash columnchromatography (hexanes to 95:5 hexanes/EtOAc; then hexanes to 65:35hexanes/DCM) afforded 12m as a cream-colored solid (30.5 mg, 5% yield).R_(f)=0.26 (hexanes/EtOAc 95:5 v/v). ¹H NMR (400 MHz, CDCl₃) δ 8.22-8.18(m, 1H), 8.08 (d, J=2.5 Hz, 1H), 7.90-7.86 (m, 1H), 7.64 (d, J=8.3 Hz,1H), 7.57-7.48 (m, 3H), 7.37 (app t, J=7.9 Hz, 1H), 6.86 (dd, J=7.5, 0.6Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 3.75 (s, 3H). ¹³C NMR (101 MHz, CDCl₃)δ 165.2, 156.2, 152.9, 136.5, 135.1, 134.7, 127.9, 126.9, 126.6, 126.4,125.8, 124.3, 124.0, 122.1, 121.7, 115.7, 113.1, 52.6. MS (ESI⁺)calculated for [C₁₈H₁₃BrNaO₃]⁺ [M+Na]⁺, 379.0; found 379.0.

Methyl 5-bromo-2-((4-ethylnaphthalen-2-yl)oxy)benzoate (12o)

Phenyl bromide 12o was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (404 mg, 1.18 mmol), naphthol 34o (170 mg,0.987 mmol), Cs₂CO₃ (643 mg, 1.97 mmol), (CuOTf)_(z)PhH (37.3 mg, 0.0740mmol), 1-naphthoic acid (255 mg, 1.48 mmol), and 4 Å molecular sieves(500 mg) in anhydrous toluene (2.5 mL). Purification by flash columnchromatography (hexanes to 95:5 hexanes/EtOAc) afforded 12o as abrownish-yellow oil (90.3 mg, 24% yield). R_(f)=0.29 (hexanes/EtOAc 95:5v/v). ¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J=2.5 Hz, 1H), 8.04-8.00 (m,1H), 7.71-7.67 (m, 1H), 7.56 (dd, J=8.8, 2.6 Hz, 1H), 7.47-7.43 (m, 2H),7.15 (d, J=2.4 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H),3.83 (s, 3H), 3.11 (q, J=7.5 Hz, 2H), 1.39 (t, J=7.5 Hz, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 164.9, 155.7, 154.7, 143.4, 136.5, 134.9, 134.7,128.9, 128.2, 126.5, 124.9, 124.7, 123.9, 122.6, 118.5, 116.0, 111.9,52.6, 25.9, 14.8. MS (ESI⁺) calculated for [C₂₀H₁₈BrO₃]⁺ [M+H]⁺, 385.0;found 385.0.

Methyl 5-bromo-2-((5-ethylnaphthalen-2-yl)oxy)benzoate (12p)

Phenyl bromide 12p was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (409 mg, 1.20 mmol), naphthol 34p (172 mg,1.00 mmol), Cs₂CO₃ (651 mg, 2.00 mmol), (CuOTO₂PhH (37.7 mg, 0.0750mmol), 1-naphthoic acid (258 mg, 1.50 mmol), and 4 Å molecular sieves(500 mg) in anhydrous toluene (2.5 mL). Purification by flash columnchromatography (hexanes to 95:5 hexanes/EtOAc) afforded 12p as a yellowoil (79.2 mg, 21% yield). R_(f)=0.24 (hexanes/EtOAc 95:5 v/v). ¹H NMR(400 MHz, CDCl₃) δ 8.09-8.04 (m, 2H), 7.59-7.53 (m, 2H), 7.41-7.36 (m,1H), 7.30-7.22 (m, 3H), 6.92 (d, J=8.8 Hz, 1H), 3.82 (s, 3H), 3.10 (q,J=7.5 Hz, 2H), 1.38 (t, J=7.5 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 165.0,155.6, 154.7, 140.6, 136.6, 134.9, 134.7, 128.7, 126.8, 126.3, 125.8,124.8, 124.2, 122.7, 119.2, 116.1, 114.5, 52.6, 26.1, 15.2. MS (ESI⁺)calculated for [C₂₀H₁₈BrO₃]⁺ [M+H]⁺, 385.0; found 385.0.

Methyl 5-bromo-2-((7-ethylnaphthalen-2-yl)oxy)benzoate (12q)

Phenyl bromide 12q was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (470 mg, 1.38 mmol), naphthol 34q (198 mg,1.15 mmol), Cs₂CO₃ (749 mg, 2.30 mmol), (CuOTf)₂.PhH (43.4 mg, 0.0863mmol), 1-naphthoic acid (297 mg, 1.72 mmol), and 4 Å molecular sieves(550 mg) in anhydrous toluene (2.5 mL). Purification by flash columnchromatography (hexanes to 95:5 hexanes/EtOAc) afforded 12q as an amberoil (96.0 mg, 20% yield). R_(f)=0.33 (hexanes/EtOAc 95:5 v/v). ¹H NMR(400 MHz, CDCl₃) δ 8.08 (d, J=2.5 Hz, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.74(d, J=8.4 Hz, 1H), 7.56 (dd, J=8.8, 2.5 Hz, 1H), 7.48 (s, 1H), 7.29 (dd,J=8.4, 1.2 Hz, 1H), 7.20-7.15 (m, 2H), 6.91 (d, J=8.8 Hz, 1H), 3.81 (s,3H), 2.78 (q, J=7.6 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H). ¹³C NMR (101 MHz,CDCl₃) δ 165.0, 155.7, 155.2, 142.9, 136.5, 134.7, 134.6, 129.9, 128.9,127.8, 126.4, 125.1, 124.8, 122.7, 118.7, 116.1, 113.4, 52.6, 29.2,15.6. MS (ESI⁺) calculated for [C₂₀H₁₇BrNaO₃]⁺ [M+Na]⁺, 407.0; found407.0.

Methyl 5-bromo-2-((4-cyclopropylnaphthalen-2-yl)oxy)benzoate (12r)

Phenyl bromide 12r was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (517 mg, 1.52 mmol), naphthol 40r (233 mg,1.26 mmol), Cs₂CO₃ (824 mg, 2.53 mmol), (CuOTf)_(z)PhH (47.7 mg, 0.0948mmol), 1-naphthoic acid (327 mg, 1.90 mmol), and 4 Å molecular sieves(1.00 g) in anhydrous toluene (5 mL). Purification by flash columnchromatography (hexanes to 95:5 hexanes/EtOAc) afforded 12r as a brownsolid (62.1 mg, 12% yield). R_(f)=0.23 (hexanes/EtOAc 95:5 v/v). ¹H NMR(400 MHz, CDCl₃) δ 8.38-8.34 (m, 1H), 8.07 (d, J=2.5 Hz, 1H), 7.71-7.66(m, 1H), 7.55 (dd, J=8.8, 2.6 Hz, 1H), 7.50-7.45 (m, 2H), 7.07-7.04 (m,2H), 6.88 (d, J=8.8 Hz, 1H), 3.82 (s, 3H), 2.41-2.32 (m, 1H), 1.12-1.05(m, 2H), 0.81-0.73 (m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 165.0, 155.7,154.7, 142.5, 136.5, 134.7, 134.6, 133.8, 130.7, 128.0, 126.7, 124.9,124.6, 122.5, 117.6, 116.0, 112.2, 52.6, 13.4, 6.9. MS (ESI⁺) calculatedfor [C₂₁H₁₇BrNaO₃]⁺ [M+Na]⁺, 419.0; found 419.0.

Methyl 5-bromo-2-((4-cyclopropyl-7-ethylnaphthalen-2-yl)oxy)benzoate(12s)

Phenyl bromide 12s was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (345 mg, 1.01 mmol), naphthol 40s (179 mg,0.842 mmol), Cs₂CO₃ (549 mg, 1.68 mmol), (CuOTf)₂.PhH (31.8 mg, 0.0632mmol), 1-naphthoic acid (218 mg, 1.26 mmol), and 4 Å molecular sieves(900 mg) in anhydrous toluene (5 mL). Purification by flash columnchromatography (hexanes to 95:5 hexanes/EtOAc) afforded 12s as a yellowsolid (48.4 mg, 14% yield). R_(f)=0.32 (hexanes/EtOAc 95:5 v/v). ¹H NMR(400 MHz, CDCl₃) δ 8.27 (d, J=8.6 Hz, 1H), 8.06 (d, J=2.5 Hz, 1H), 7.54(dd, J=8.8, 2.5 Hz, 1H), 7.47 (s, 1H), 7.34 (dd, J=8.5, 1.3 Hz, 1H),7.00 (d, J=2.1 Hz, 1H), 6.98 (d, J=2.1 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H),3.82 (s, 3H), 2.78 (q, J=7.6 Hz, 2H), 2.39-2.30 (m, 1H), 1.31 (t, J=7.6Hz, 3H), 1.10-1.03 (m, 2H), 0.79-0.73 (m, 2H). ¹³C NMR (126 MHz, CDCl₃)δ 165.0, 155.9, 154.7, 142.7, 142.3, 136.5, 134.9, 134.7, 129.1, 126.1,125.8, 124.6, 124.5, 122.4, 116.7, 115.8, 112.0, 52.6, 29.0, 15.6, 13.4,6.9. MS (ESI⁺) calculated for [C₂₃H₂₂BrO₃]⁺ [M+H]⁺, 425.1; found 425.0.

Methyl 2-([1,1′-biphenyl]-4-yloxy)-5-bromobenzoate (12t)

Phenyl bromide 12t was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (481 mg, 1.41 mmol), 4-phenylphenol (200mg, 1.18 mmol), Cs₂CO₃ (766 mg, 2.35 mmol), (CuOTf)₂.PhH (44.4 mg,0.0881 mmol), 1-naphthoic acid (304 mg, 1.76 mmol), and 4 Å molecularsieves (1.00 g) in anhydrous toluene (5 mL). Purification by flashcolumn chromatography (hexanes to 95:5 hexanes/EtOAc) afforded 12t as abright yellow solid (127 mg, 28% yield). R_(f)=0.23 (hexanes/EtOAc 95:5v/v). ¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, J=2.5 Hz, 1H), 7.60-7.53 (m,5H), 7.43 (t, J=7.6 Hz, 2H), 7.34 (t, J=7.3 Hz, 1H), 7.03 (d, J=8.6 Hz,2H), 6.93 (d, J=8.8 Hz, 1H), 3.84 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ164.9, 156.8, 155.6, 140.5, 136.8, 136.5, 134.7, 129.0, 128.7, 127.3,127.1, 124.9, 122.6, 118.7, 116.1, 52.6. MS (ESI⁺) calculated for[C₂₀H₁₅BrNaO₃]⁺ [M+Na]⁺, 405.0; found 405.0.

Methyl 2-([1,1′-biphenyl]-3-yloxy)-5-bromobenzoate (12u)

Phenyl bromide 12u was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (481 mg, 1.41 mmol), 3-phenylphenol (200mg, 1.18 mmol), Cs₂CO₃ (766 mg, 2.35 mmol), (CuOTf)₂.PhH (44.4 mg,0.0881 mmol), 1-naphthoic acid (304 mg, 1.76 mmol), and 4 Å molecularsieves (1.00 g) in anhydrous toluene (5 mL). Purification by flashcolumn chromatography (hexanes to 95:5 hexanes/EtOAc) afforded 12u as apale yellow oil (161 mg, 36% yield). R_(f)=0.23 (hexanes/EtOAc 95:5v/v). ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J=2.4 Hz, 1H), 7.59-7.52 (m,3H), 7.47-7.39 (m, 3H), 7.39-7.32 (m, 2H), 7.21 (app t, J=1.7 Hz, 1H),6.97-6.89 (m, 2H), 3.84 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 165.0,157.6, 155.7, 143.4, 140.4, 136.5, 134.7, 130.3, 129.0, 128.7, 127.9,127.2, 122.6, 122.4, 118.7, 117.3, 116.0, 52.6. MS (ESI⁺) calculated for[C₂₀H₁₅BrNaO₃]⁺ [M+Na]⁺, 405.0; found 405.0.

Methyl 5-bromo-2-((3′,5′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)benzoate(12v)

Phenyl bromide 12v was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (298 mg, 1.22 mmol), phenol 45v (202 mg,1.02 mmol), Cs₂CO₃ (664 mg, 2.04 mmol), (CuOTf)_(z)PhH (38.5 mg, 0.0764mmol), 1-naphthoic acid (263 mg, 1.53 mmol), and 4 Å molecular sieves(1.00 g) in anhydrous toluene (6 mL). Purification by flash columnchromatography (hexanes to 95:5 hexanes/EtOAc) afforded 12v as a clearoil (55.8 mg, 13% yield). R_(f)=0.50 (hexanes/EtOAc 95:5 v/v). ¹H NMR(400 MHz, CDCl₃) δ 8.04 (d, J=2.4 Hz, 1H), 7.54 (dd, J=8.8, 2.5 Hz, 1H),7.41-7.32 (m, 2H), 7.20 (app t, J=2.0 Hz, 1H), 7.17 (s, 2H), 7.00 (s,1H), 6.94-6.91 (m, 1H), 6.89 (d, J=8.8 Hz, 1H), 3.85 (s, 3H), 2.37 (s,6H). ¹³C NMR (101 MHz, CDCl₃) δ 165.1, 157.3, 155.9, 143.7, 140.4,138.5, 136.5, 134.6, 130.2, 129.5, 125.1, 124.6, 122.8, 122.1, 117.6,117.3, 115.7, 52.6, 21.5. MS (ESI⁺) calculated for [C₂₂H₁₉BrNaO₃]⁺[M+Na]⁺, 433.0; found 433.0.

Methyl 5-bromo-2-((4′-ethoxy-[1,1′-biphenyl]-3-yl)oxy)benzoate (12w)

Phenyl bromide 12w was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (361 mg, 1.06 mmol), phenol 45w (189 mg,0.883 mmol), Cs₂CO₃ (575 mg, 1.77 mmol), (CuOTf)₂.PhH (33.3 mg, 0.0662mmol), 1-naphthoic acid (228 mg, 1.32 mmol), and 4 Å molecular sieves(1.00 g) in anhydrous toluene (5 mL). Purification by flash columnchromatography (hexanes to 95:5 hexanes/EtOAc) afforded 12w as a yellowsolid (85.5 mg, 23% yield). R_(f)=0.18 (hexanes/EtOAc 95:5 v/v). ¹H NMR(400 MHz, CDCl₃) δ 8.04 (d, J=2.5 Hz, 1H), 7.54 (dd, J=8.8, 2.5 Hz, 1H),7.47 (d, J=8.7 Hz, 2H), 7.37 (app t, J=7.8 Hz, 1H), 7.31 (d, J=7.8 Hz,1H), 7.17 (app t, J=1.9 Hz, 1H), 6.94 (d, J=8.7 Hz, 2H), 6.92-6.86 (m,2H), 4.07 (q, J=7.0 Hz, 2H), 3.84 (s, 3H), 1.43 (t, J=7.0 Hz, 3H). ¹³CNMR (151 MHz, CDCl₃) δ 165.0, 159.0, 157.5, 155.8, 143.0, 136.5, 134.6,132.7, 130.2, 128.2, 124.6, 122.3, 122.2, 116.9, 116.8, 115.8, 114.9,63.7, 52.6, 15.0. MS (ESI⁺) calculated for [C₂₂H₂₀BrO₄]⁺ [M+H]⁺, 427.0;found 426.9.

Methyl5-bromo-2-((4′-(3-morpholinopropoxy)-[1,1′-biphenyl]-3-yl)oxy)benzoate(12x)

Phenyl bromide 12x was prepared according to the procedure for 12a usingmethyl 5-bromo-2-iodobenzoate (872 mg, 2.56 mmol), phenol 48 (668 mg,2.13 mmol), Cs₂CO₃ (1.39 g, 4.26 mmol), (CuOTf)₂.PhH (80.5 mg, 0.180mmol), 1-naphthoic acid (551 mg, 3.20 mmol), and 4 Å molecular sieves(1.00 g) in anhydrous toluene (7 mL). Purification by flash columnchromatography (DCM to EtOAc with 2% MeOH throughout) afforded 12x as abrown solid (166 mg, 15% yield). R_(f)=0.42 (DCM/EtOAc/MeOH 47.5:47.5:5v/v/v). ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J=2.5 Hz, 1H), 7.54 (dd,J=8.8, 2.5 Hz, 1H), 7.47 (d, J=8.7 Hz, 2H), 7.37 (app t, J=7.9 Hz, 1H),7.30 (d, J=7.8 Hz, 1H), 7.16 (t, J=2.0 Hz, 1H), 6.95 (d, J=8.7 Hz, 2H),6.92-6.86 (m, 2H), 4.06 (t, J=6.3 Hz, 2H), 3.84 (s, 3H), 3.74 (t, J=4.7Hz, 4H), 2.57 (t, J=7.1 Hz, 2H), 2.54-2.47 (m, 4H), 2.01 (app quint,J=6.7 Hz, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 165.0, 159.0, 157.5, 155.8,143.0, 136.5, 134.6, 132.8, 130.3, 128.3, 124.7, 122.3, 122.2, 116.9,116.8, 115.9, 115.0, 67.0, 66.3, 55.7, 53.8, 52.6, 26.5. MS (ESI⁺)calculated for [C₂₇H₂₉BrNO₅]⁺ [M+H]⁺, 526.1; found 526.1.

Synthesis of 12k Methyl 2-((adamantan-2-yl)oxy)-5-bromobenzoate (12k)

To a solution of methyl 5-bromosalicylate (500 mg, 2.16 mmol) andtriphenylphosphine (681 mg, 2.60 mmol) in anhydrous THF (10 mL) wasadded 2-adamantol (395 mg, 2.60 mmol). The solution was brought toreflux and diisopropyl azodicarboxylate (dissolved in 1.5 mL THF, 525mg, 2.60 mmol) was added over 45 minutes. After 17 hours at reflux, thereaction mixture was concentrated under vacuum. The residue wasdissolved in EtOAc (100 mL) and washed with brine (100 mL). The organicphase was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. Purification by flash column chromatography (hexanes to 95:5hexanes/EtOAc) afforded 12k as a foggy white oil (613 mg, 78% yield).R_(f)=0.51 (hexanes/EtOAc 90:10 v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.89 (d,J=2.6 Hz, 1H), 7.47 (dd, J=8.9, 2.6 Hz, 1H), 6.84 (d, J=8.9 Hz, 1H),4.48 (app t, J=3.1 Hz, 1H), 3.89 (s, 3H), 2.25-2.13 (m, 4H), 1.96-1.85(m, 4H), 1.80-1.71 (m, 4H), 1.53 (d, J=12.1 Hz, 2H). ¹³C NMR (101 MHz,CDCl₃) δ 166.0, 156.3, 135.8, 134.5, 123.0, 116.4, 111.7, 80.8, 52.3,37.5, 36.4, 31.5, 31.5, 27.4, 27.2. MS (ESI⁺) calculated for[C₁₈H₂₁BrNaO₃]⁺ [M+Na]⁺, 387.0; found 387.1.

Synthesis of 13a-c, 14a, 14b, 15a-g, and 15i-15x Methyl4-(1H-pyrazol-4-yl)-[1,1′-biphenyl]-2-carboxylate (13a)

To a microwave vial were added phenyl bromide 10a (75.3 mg, 0.259 mmol)and 4-pyrazoleboronic acid pincol ester (50.2 mg, 0.259 mmol). Thestarting materials were fully dissolved in dioxane (2.5 mL) and water (1mL) before the addition of Cs₂CO₃ (253 mg, 0.776 mmol) andPd(dppf)Cl₂.DCM (21.1 mg, 0.0259 mmol). The mixture was degassed with N₂for 7 minutes and heated with microwave irradiation at 100° C. for 3hours. The reaction mixture was diluted with EtOAc (100 mL) and washedwith brine (100 mL). The organic phase was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. Purification by flash columnchromatography (DCM to EtOAc) afforded 13a as a white solid (18.8 mg.26% yield). R_(f)=0.38 (DCM/EtOAc 50:50 v/v). ¹H NMR (400 MHz, DMSO-d₆)δ 13.06 (br s, 1H), 8.35 (s, 1H), 8.03 (s, 1H), 7.92 (s, 1H), 7.85 (d,J=8.0 Hz, 1H), 7.46-7.33 (m, 4H), 7.30 (d, J=7.5 Hz, 2H), 3.60 (s, 3H).¹³C NMR (101 MHz, DMSO-d₆) δ 168.9, 140.2, 138.1, 132.3, 131.7, 130.9,128.3, 128.0, 127.8, 127.3, 126.1, 125.4, 119.9, 52.0. MS (ESI⁺)calculated for [C₁₇H₁₈N₂O₂]⁺ [M+H]⁺, 279.1; found 279.1.

Methyl 2-(naphthalen-1-yl)-5-(1H-pyrazol-4-yl)benzoate (13b)

Methyl ester 13b was prepared according to the procedure for 13a usingphenyl bromide 10b (100 mg, 0.293 mmol), 4-pyrazoleboronic acid pincolester (56.9 mg, 0.293 mmol), Cs₂CO₃ (287 mg, 0.879 mmol), andPd(dppf)Cl₂.DCM (23.9 mg, 0.0293 mmol) in dioxane (2.5 mL) and water (1mL). Purification by flash column chromatography (DCM to EtOAc) afforded13b as a white solid (23.5 mg, 24% yield). R_(f)=0.40 (DCM/EtOAc 50:50v/v). ¹H NMR (400 MHz, DMSO-d₆) δ 13.09 (br s, 1H), 8.39 (s, 1H), 8.12(s, 1H), 8.07 (s, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.93 (d, J=8.0 Hz, 2H),7.58-7.38 (m, 5H), 7.32 (d, J=6.9 Hz, 1H), 3.33 (s, 3H). ¹³C NMR (101MHz, DMSO-d₆) δ 167.4, 138.8, 137.4, 136.5, 133.0, 132.7, 132.2, 132.1,131.5, 128.2, 127.4, 127.4, 126.1, 126.1, 125.7, 125.7, 125.3, 125.0,120.0, 51.7. MS (ESI⁺) calculated for [C₂₁H₁₇N₂O₂]⁺ [M+H]⁺, 329.1; found329.1.

Methyl 2-(naphthalen-2-yl)-5-(1H-pyrazol-4-yl)benzoate (13c)

Methyl ester 13c was prepared according to the procedure for 13a usingphenyl bromide 10c (100 mg, 0.293 mmol), 4-pyrazoleboronic acid pincolester (56.9 mg, 0.293 mmol), Cs₂CO₃ (287 mg, 0.879 mmol), andPd(dppf)Cl₂.DCM (23.9 mg, 0.0293 mmol) in dioxane (2.5 mL) and water (1mL). Purification by flash column chromatography (DCM to EtOAc) afforded13c as a yellow solid (24.3 mg, 25% yield). R_(f)=0.41 (DCM/EtOAc 50:50v/v). ¹H NMR (400 MHz, DMSO-d₆) δ 13.08 (br s, 1H), 8.38 (s, 1H), 8.06(s, 1H), 8.02-7.85 (m, 6H), 7.59-7.51 (m, 3H), 7.43 (d, J=9.3 Hz, 1H),3.59 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 168.8, 138.2, 137.9, 136.5,133.0, 132.4, 132.0, 131.7, 131.3, 128.1, 127.9, 127.6, 127.5, 126.8,126.5, 126.4, 126.2, 125.6, 119.9, 52.1. MS (ESI⁺) calculated for[C₂₁H₁₇N₂O₂]⁺ [M+H]⁺, 329.1; found 329.2.

Methyl 2-(phenylamino)-5-(1H-pyrazol-4-yl)benzoate (14a)

Methyl ester 14a was prepared according to the procedure for 13a usingphenyl bromide 11a (139 mg, 0.454 mmol), 4-pyrazoleboronic acid pincolester (88.1 mg, 0.454 mmol), Cs₂CO₃ (444 mg, 1.36 mmol), andPd(dppf)Cl₂.DCM (37.1 mg, 0.0454 mmol) in dioxane (2.5 mL) and water (1mL). Purification by flash column chromatography (DCM to EtOAc) afforded14a as a yellow oil (28.0 mg, 21% yield). R_(f)=0.40 (DCM/EtOAc 50:50v/v). ¹H NMR (400 MHz, CDCl₃) δ 9.44 (br s, 1H), 8.11 (s, 1H), 7.83 (s,2H), 7.64 (s, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.35 (t, J=7.6 Hz, 2H), 7.30(d, J=8.8 Hz, 1H), 7.24 (s, 1H), 7.09 (t, J=7.3 Hz, 1H), 3.93 (s, 3H).¹³C NMR (101 MHz, CDCl₃) δ 168.9, 146.6, 140.9, 131.9, 130.7, 129.6,129.5, 128.6, 123.6, 122.4, 121.8, 114.9, 112.4, 52.0. MS (ESI⁺)calculated for [C₁₇H₁₆N₃O₂]⁺ [M+H]⁺, 294.1; found 294.1.

Methyl 2-(methyl(naphthalen-2-yl)amino)-5-(1H-pyrazol-4-yl)benzoate(14b)

Methyl ester 14b was prepared according to the procedure for 13a usingphenyl bromide 11b (47.6 mg, 0.129 mmol), 4-pyrazoleboronic acid pincolester (24.9 mg, 0.129 mmol), Cs₂CO₃ (126 mg, 0.387 mmol), andPd(dppf)Cl₂.DCM (10.5 mg, 0.0129 mmol) in dioxane (2.5 mL) and water (1mL). Purification by flash column chromatography (DCM to EtOAc with 2%MeOH throughout) afforded 14b as a yellow oil (20.0 mg, 44% yield).R_(f)=0.56 (DCM/EtOAc/MeOH 47.5:47.5:5 v/v/v). ¹H NMR (400 MHz, CDCl₃) δ7.98 (s, 1H), 7.92 (s, 2H), 7.71-7.62 (m, 3H), 7.57 (d, J=9.0 Hz, 1H),7.40-7.30 (m, 2H), 7.22 (app t, J=7.3 Hz, 1H), 7.01 (s, 1H), 6.88 (d,J=9.0 Hz, 1H), 3.57 (s, 3H), 3.40 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ167.5, 147.0, 146.4, 134.9, 131.5, 130.5, 129.9, 129.8, 128.7, 128.6,128.6, 127.7, 127.6, 126.5, 126.4, 126.4, 122.7, 117.8, 108.1, 52.4,40.8. MS (ESI⁺) calculated for [C₂₂H₂₀N₃O₂]⁺ [M+H]⁺, 358.2; found 358.2.

Methyl 2-phenoxy-5-(1H-pyrazol-4-yl)benzoate (15a)

Methyl ester 15a was prepared according to the procedure for 13a usingphenyl bromide 12a (105 mg, 0.307 mmol), 4-pyrazoleboronic acid pincolester (59.5 mg, 0.307 mmol), Cs₂CO₃ (300 mg, 0.921 mmol), andPd(dppf)Cl₂.DCM (25.1 mg, 0.0307 mmol) in dioxane (2.5 mL) and water (1mL). Purification by flash column chromatography (DCM to EtOAc) afforded15a as a brown solid (26.0 mg, 26% yield). R_(f)=0.30 (DCM/EtOAc 50:50v/v). ¹H NMR (400 MHz, DMSO-d₆) δ 13.01 (br s, 1H), 8.11 (s, 2H), 8.00(d, J=2.0 Hz, 1H), 7.82 (dd, J=8.5, 2.0 Hz, 1H), 7.36 (t, J=7.8 Hz, 2H),7.15-7.03 (m, 2H), 6.98-6.90 (m, 2H), 3.72 (s, 3H). ¹³C NMR (101 MHz,DMSO-d₆) δ 165.5, 157.6, 152.6, 130.4, 129.9, 129.3, 127.3, 123.8,122.9, 121.9, 119.7, 117.9, 117.3, 52.1. MS (ESI⁺) calculated for[C₁₇H₁₅N₂O₃]⁺ [M+H]⁺, 295.1; found 295.1.

Methyl 5-(1H-pyrazol-4-yl)-2-(o-tolyloxy)benzoate (15b)

Methyl ester 15b was prepared according to the procedure for 13a usingphenyl bromide 12b (116 mg, 0.360 mmol), 4-pyrazoleboronic acid pincolester (69.9 mg, 0.360 mmol), Cs₂CO₃ (352 mg, 1.08 mmol), andPd(dppf)Cl₂.DCM (29.4 mg, 0.0360 mmol) in dioxane (2.5 mL) and water (1mL). Purification by flash column chromatography (DCM to EtOAc with 2%MeOH throughout) afforded 15b as a brown wax (24.5 mg, 22% yield).R_(f)=0.41 (DCM/EtOAc/MeOH 47.5:47.5:5 v/v/v). ¹H NMR (600 MHz, DMSO-d₆)δ 13.01 (br s, 1H), 8.08 (s, 2H), 7.99 (app t, J=1.2 Hz, 1H), 7.79-7.75(m, 1H), 7.30 (d, J=7.2 Hz, 1H), 7.16 (app t, J=7.6 Hz, 1H), 7.05 (appt, J=7.2 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 6.74 (d, J=7.9 Hz, 1H), 3.74(s, 3H), 2.22 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 165.7, 154.8, 153.3,131.4, 130.3, 128.4, 128.2, 127.4, 127.3, 123.6, 123.5, 122.7, 119.8,119.7, 117.4, 52.1, 15.8. MS (ESI⁺) calculated for [C₁₈H₁₇N₂O₃]⁺ [M+H]⁺,309.1; found 309.2.

Methyl 5-(1H-pyrazol-4-yl)-2-(m-tolyloxy)benzoate (15c)

Methyl ester 15c was prepared according to the procedure for 13a usingphenyl bromide 12c (103 mg, 0.321 mmol), 4-pyrazoleboronic acid pincolester (62.2 mg, 0.321 mmol), Cs₂CO₃ (314 mg, 0.962 mmol), andPd(dppf)Cl₂.DCM (26.2 mg, 0.0321 mmol) in dioxane (2.5 mL) and water (1mL). Purification by flash column chromatography (DCM to EtOAc with 2%MeOH throughout) afforded 15c as a brownish-orange wax (25.2 mg, 25%yield). R_(f)=0.45 (DCM/EtOAc/MeOH 47.5:47.5:5 v/v/v). ¹H NMR (400 MHz,DMSO-d₆) δ 13.02 (br s, 1H), 8.10 (s, 2H), 7.99 (d, J=2.1 Hz, 1H), 7.81(dd, J=8.6, 2.1 Hz, 1H), 7.23 (app t, J=7.8 Hz, 1H), 7.03 (d, J=8.5 Hz,1H), 6.91 (d, J=7.5 Hz, 1H), 6.76 (s, 1H), 6.72 (d, J=8.2 Hz, 1H), 3.73(s, 3H), 2.27 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 165.5, 157.5, 152.7,139.6, 130.3, 129.6, 129.1, 127.2, 123.8, 123.7, 121.7, 119.7, 118.5,117.9, 114.5, 52.1, 21.0. MS (ESI⁺) calculated for [C₁₈H₁₇N₂O₃]⁺ [M+H]⁺,309.1; found 309.2.

Methyl 5-(1H-pyrazol-4-yl)-2-(p-tolyloxy)benzoate (15d)

Methyl ester 15d was prepared according to the procedure for 13a usingphenyl bromide 12d (103 mg, 0.321 mmol), 4-pyrazoleboronic acid pincolester (62.2 mg, 0.321 mmol), Cs₂CO₃ (314 mg, 0.962 mmol), andPd(dppf)Cl₂.DCM (26.2 mg, 0.0321 mmol) in dioxane (2.5 mL) and water (1mL). Purification by flash column chromatography (DCM to EtOAc with 2%MeOH throughout) afforded 15d as an orange wax (21.1 mg, 21% yield).R_(f)=0.38 (DCM/EtOAc/MeOH 47.5:47.5:5 v/v/v). ¹H NMR (400 MHz, DMSO-d₆)δ 13.01 (br s, 1H), 8.09 (s, 2H), 7.98 (d, J=2.1 Hz, 1H), 7.79 (dd,J=8.5, 2.2 Hz, 1H), 7.16 (d, J=8.1 Hz, 2H), 6.99 (d, J=8.5 Hz, 1H), 6.84(d, J=8.5 Hz, 2H), 3.73 (s, 3H), 2.27 (s, 3H). ¹³C NMR (101 MHz,DMSO-d₆) δ 165.6, 155.2, 153.1, 132.0, 130.3, 130.2, 128.8, 127.2,123.5, 121.1, 119.7, 118.2, 117.6, 52.1, 20.2. MS (ESI⁺) calculated for[C₁₈H₁₇N₂O₃]⁺ [M+H]⁺, 309.1; found 309.2.

Methyl 2-(3-fluorophenoxy)-5-(1H-pyrazol-4-yl)benzoate (15e)

Methyl ester 15e was prepared according to the procedure for 13a usingphenyl bromide 12e (82.9 mg, 0.259 mmol), 4-pyrazoleboronic acid pincolester (50.3 mg, 0.259 mmol), Cs₂CO₃ (253 mg, 0.777 mmol), andPd(dppf)Cl₂.DCM (21.2 mg, 0.0259 mmol) in dioxane (2.5 mL) and water (1mL). Purification by flash column chromatography (DCM to EtOAc with 2%MeOH throughout) afforded 15e as an off-white solid (14.9 mg, 18%yield). R_(f)=0.42 (DCM/EtOAc/MeOH 47.5:47.5:5 v/v/v). ¹H NMR (400 MHz,DMSO-d₆) δ 13.02 (br s, 1H), 8.29 (s, 1H), 8.04 (s, 1H), 7.97 (s, 1H),7.87 (d, J=6.4 Hz, 1H), 7.37 (app q, J=7.4 Hz, 1H), 7.17 (d, J=8.4 Hz,1H), 6.92 (app t, J=9.3 Hz, 1H), 6.77 (d, J=10.6 Hz, 1H), 6.72 (d, J=7.3Hz, 1H), 3.71 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 165.2, 162.8 (d,J=244.1 Hz), 159.3 (d, J=11.3 Hz), 151.6, 131.1 (d, J=10.0 Hz), 130.6,130.1, 127.4, 124.0, 122.7, 119.6, 112.7 (d, J=2.9 Hz), 109.5, 109.3 (d,J=21.1 Hz), 104.5 (d, J=24.9 Hz), 52.2. MS (ESI⁺) calculated for[C₁₇H₁₇N₂O₃]⁺ [M+H]⁺, 313.1; found 313.2.

Methyl 2-(4-fluorophenoxy)-5-(1H-pyrazol-4-yl)benzoate (15f)

Methyl ester 15f was prepared according to the procedure for 13a usingphenyl bromide 12f (105 mg, 0.321 mmol), 4-pyrazoleboronic acid pincolester (62.4 mg, 0.321 mmol), Cs₂CO₃ (314 mg, 0.964 mmol), andPd(dppf)Cl₂.DCM (26.2 mg, 0.0321 mmol) in dioxane (2.5 mL) and water (1mL). Purification by flash column chromatography (DCM to EtOAc with 2%MeOH throughout) afforded 15f as a yellow oil (20.5 mg, 20% yield).R_(f)=0.40 (DCM/EtOAc/MeOH 47.5:47.5:5 v/v/v). ¹H NMR (400 MHz, DMSO-d₆)δ 13.00 (br s, 1H), 8.12 (s, 2H), 8.00 (d, J=2.1 Hz, 1H), 7.82 (dd,J=8.5, 2.1 Hz, 1H), 7.19 (t, J=8.7 Hz, 2H), 7.04 (d, J=8.5 Hz, 1H),7.01-6.94 (m, 2H), 3.74 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 165.5,157.8 (d, J=238.7 Hz), 153.7 (d, J=1.8 Hz), 152.9, 136.1, 130.4, 129.2,127.3, 123.6, 121.4, 119.6, 119.2 (d, J=8.4 Hz), 116.4 (d, J=23.4 Hz),52.2. MS (ESI⁺) calculated for [C₁₇H₁₄FN₂O₃]⁺ [M+H]⁺, 313.1; found313.2.

Methyl 2-(naphthalen-2-yloxy)-5-(1H-pyrazol-4-yl)benzoate (15g)

Methyl ester 15g was prepared according to the procedure for 13a usingphenyl bromide 12g (78.3 mg, 0.219 mmol), 4-pyrazoleboronic acid pincolester (42.5 mg, 0.219 mmol), Cs₂CO₃ (214 mg, 0.658 mmol), andPd(dppf)Cl₂.DCM (17.9 mg, 0.0219 mmol) in dioxane (2.5 mL) and water (1mL). Purification by flash column chromatography (DCM to EtOAc) afforded15g as a clear oil (9.9 mg, 13% yield). R_(f)=0.35 (DCM/EtOAc 50:50v/v). ¹H NMR (600 MHz, CDCl₃) δ 8.11 (d, J=2.1 Hz, 1H), 7.91 (s, 2H),7.84 (d, J=8.9 Hz, 1H), 7.82 (d, J=8.1 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H),7.63 (dd, J=8.5, 2.1 Hz, 1H), 7.44 (app t, J=7.4 Hz, 1H), 7.39 (app t,J=7.4 Hz, 1H), 7.29 (dd, J=8.9, 2.3 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H),7.09 (d, J=8.4 Hz, 1H), 3.81 (s, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 166.3,155.9, 154.6, 134.4, 131.4, 131.0, 130.1, 130.1, 129.2, 128.7, 127.9,127.2, 126.7, 124.8, 123.8, 122.2, 121.4, 119.5, 112.9, 52.5. MS (ESI⁺)calculated for [C₂₁H₁₇N₂O₃]⁺ [M+H]⁺, 345.1; found 345.1.

Methyl 2-(phenanthren-9-yloxy)-5-(1H-pyrazol-4-yl)benzoate (15j)

Methyl ester 15j was prepared according to the procedure for 13a usingphenyl bromide 12j (50.0 mg, 0.123 mmol), 4-pyrazoleboronic acid pincolester (23.8 mg, 0.123 mmol), Cs₂CO₃ (120 mg, 0.368 mmol), andPd(dppf)Cl₂.DCM (10.0 mg, 0.0123 mmol) in dioxane (2.5 mL) and water (1mL). Purification by flash column chromatography (DCM to EtOAc with 2%MeOH throughout) afforded 15j as a white solid (9.1 mg, 19% yield).R_(f)=0.50 (DCM/EtOAc/MeOH 47.5:47.5:5 v/v/v). ¹H NMR (600 MHz, DMSO-d₆)δ 13.04 (br s, 1H), 8.90 (d, J=8.3 Hz, 1H), 8.79 (d, J=8.1 Hz, 1H), 8.36(d, J=8.1 Hz, 1H), 8.31 (s, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.89 (d,J=8.4 Hz, 1H), 7.83-7.78 (m, 2H), 7.75 (app t, J=7.5 Hz, 1H), 7.59 (appt, J=7.4 Hz, 1H), 7.55 (app t, J=7.5 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H),7.01 (s, 1H), 3.59 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 165.4, 152.5,151.9, 131.8, 131.2, 130.6, 129.7, 128.8, 127.8, 127.8, 127.6, 127.2,127.1, 126.9, 125.7, 125.5, 123.6, 123.2, 122.9, 122.3, 122.2, 119.7,108.7, 52.1. MS (ESI⁺) calculated for [C₂₅H₁₉N₂O₃]⁺ [M+H]⁺, 395.1; found395.2.

Methyl 2-((adamantan-2-yl)oxy)-5-(1H-pyrazol-4-yl)benzoate (15k)

Methyl ester 15k was prepared according to the procedure for 13a usingphenyl bromide 12k (124 mg, 0.340 mmol), 4-pyrazoleboronic acid pincolester (66.0 mg, 0.340 mmol), Cs₂CO₃ (332 mg, 1.02 mmol), andPd(dppf)Cl₂.DCM (27.8 mg, 0.0340 mmol) in dioxane (2.5 mL) and water (1mL). Purification by flash column chromatography (DCM to EtOAc with 2%MeOH throughout) afforded 15k as a clear oil (29.4 mg, 25% yield).R_(f)=0.42 (DCM/EtOAc/MeOH 47.5:47.5:5 v/v/v). ¹H NMR (600 MHz, DMSO-d₆)δ 12.90 (br s, 1H), 8.13 (s, 1H), 7.89 (s, 1H), 7.80 (d, J=2.2 Hz, 1H),7.67 (dd, J=8.6, 2.2 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 4.63 (app t, J=3.2Hz, 1H), 3.81 (s, 3H), 2.13 (d, J=12.1 Hz, 2H), 2.07 (s, 2H), 1.87-1.76(m, 6H), 1.70 (s, 2H), 1.46 (d, J=11.9 Hz, 2H). ¹³C NMR (151 MHz,DMSO-d₆) δ 166.8, 153.9, 135.8, 129.6, 127.0, 125.0, 121.8, 120.1,115.4, 78.8, 51.8, 36.9, 35.5, 30.8, 30.8, 26.8, 26.6. MS (ESI⁺)calculated for [C₂₁H₂₅N₂O₃]⁺ [M+H]⁺, 353.2; found 353.3.

Methyl2-((1,2-dihydroacenaphthylen-4-yl)oxy)-5-(1H-pyrazol-4-yl)benzoate (15l)

Methyl ester 15l was prepared according to the procedure for 13a usingphenyl bromide 12l (10.6 mg, 0.0277 mmol), 4-pyrazoleboronic acid pincolester (5.4 mg, 0.028 mmol), Cs₂CO₃ (27.0 mg, 0.0830 mmol), andPd(dppf)Cl₂DCM (2.3 mg, 0.0028 mmol) in dioxane (1.25 mL) and water (0.5mL). Purification by flash column chromatography (DCM to EtOAc with 2%MeOH throughout) afforded 151 as a white solid (2.7 mg, 26% yield).R_(f)=0.58 (DCM/EtOAc/MeOH 47.5:47.5:5 v/v/v). ¹H NMR (600 MHz, DMSO-d₆)δ 12.99 (br s, 1H), 8.26 (s, 1H), 8.04 (d, J=1.4 Hz, 1H), 7.98 (s, 1H),7.84 (d, J=8.5 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.41 (app t, J=7.5 Hz,1H), 7.22 (d, J=6.8 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.05 (s, 1H), 6.94(s, 1H), 3.72 (s, 3H), 3.37-3.34 (m, 4H). ¹³C NMR (151 MHz, DMSO-d₆) δ165.5, 158.2, 152.9, 148.3, 145.5, 135.4, 131.3, 130.5, 129.3, 128.8,127.3, 125.8, 123.9, 122.1, 121.5, 119.7, 118.1, 112.7, 107.3, 52.2,30.2, 29.7. MS (ESI⁺) calculated for [C₂₃H₁₉N₂O₃]⁺ [M+H]⁺, 371.1; found371.1.

Methyl 5-(3-fluoro-1H-pyrazol-4-yl)-2-(naphthalen-1-yloxy)benzoate (15m)

Methyl ester 15m was prepared according to the procedure for 13a usingphenyl bromide 12m (60.5 mg, 0.169 mmol), fluorinated pyrazole 16 (35.9mg, 0.169 mmol), Cs₂CO₃ (166 mg, 0.508 mmol), and Pd(dppf)Cl₂.DCM (13.8mg, 0.0169 mmol) in dioxane (2.5 mL) and water (1 mL). Purification byflash column chromatography (DCM to 30:70 DCM/EtOAc) afforded 15m as alight brown oil (15.6 mg, 24% yield). R_(f)=0.70 (DCM/EtOAc 50:50 v/v).¹H NMR (400 MHz, DMSO-d₆) δ 12.69 (br s, 1H), 8.26 (app t, J=1.9 Hz,2H), 8.20-8.14 (m, 1H), 8.06 (d, J=2.3 Hz, 1H), 8.01-7.96 (m, 1H), 7.76(dd, J=8.5, 2.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.62-7.55 (m, 2H), 7.43(app t, J=7.9 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H), 6.84 (d, J=7.3 Hz, 1H),3.65 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 165.3, 160.5 (d, J=240.5 Hz),153.6, 152.8, 134.5, 130.9, 130.9 (d, J=5.3 Hz), 128.9, 128.0 (d, J=3.7Hz), 127.8, 126.8, 126.4 (d, J=4.8 Hz), 126.2, 126.0, 125.5, 123.1,121.5, 121.2, 111.9, 102.0 (d, J=17.9 Hz), 52.2. ¹⁹F NMR (376 MHz,DMSO-d₆) δ −135.4. MS (ESI⁺) calculated for [C₂₁H₁₆FN₂O₃]⁺ [M+H]⁺,363.1; found 363.1.

Methyl 5-(3-fluoro-1H-pyrazol-4-yl)-2-(naphthalen-2-yloxy)benzoate (15n)

Methyl ester 15n was prepared according to the procedure for 13a usingphenyl bromide 12g (77.0 mg, 0.216 mmol), fluorinated pyrazole 16 (45.7mg, 0.216 mmol), Cs₂CO₃ (211 mg, 0.647 mmol), and Pd(dppf)Cl₂.DCM (17.6mg, 0.0216 mmol) in dioxane (2.5 mL) and water (1 mL). Purification byflash column chromatography (DCM to EtOAc with 2% MeOH throughout)afforded 15n as a white solid (10.5 mg, 13% yield). R_(f)=0.26(DCM/EtOAc/MeOH 47.5:47.5:5 v/v/v). ¹H NMR (400 MHz, CDCl₃) δ 9.76 (brs, 1H), 8.11 (d, J=2.3 Hz, 1H), 7.83 (app t, J=9.2 Hz, 2H), 7.71 (d,J=2.1 Hz, 1H), 7.70-7.65 (m, 2H), 7.48-7.43 (m, 1H), 7.43-7.37 (m, 1H),7.28 (dd, J=8.9, 2.4 Hz, 1H), 7.23 (d, J=2.2 Hz, 1H), 7.09 (d, J=8.6 Hz,1H), 3.82 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 166.2, 161.6 (d, J=246.2Hz), 155.6, 154.9, 134.4, 131.3 (d, J=3.7 Hz), 130.3, 130.1, 129.5 (d,J=2.9 Hz), 127.9, 127.5, 127.3, 126.7, 125.9 (d, J=4.6 Hz), 124.9,123.8, 122.0, 119.5, 113.2, 104.9 (d, J=17.7 Hz), 52.5. ¹⁹F NMR (376MHz, CDCl₃) δ −132.8. MS (ESI⁺) calculated for [C₂₁H₁₆FN₂O₃]⁺ [M+H]⁺,363.1; found 363.1.

Methyl2-((4-ethylnaphthalen-2-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoate(15o)

Methyl ester 15o was prepared according to the procedure for 13a usingphenyl bromide 12o (90.0 mg, 0.234 mmol), fluorinated pyrazole 16 (49.5mg, 0.234 mmol), Cs₂CO₃ (228 mg, 0.701 mmol), and Pd(dppf)Cl₂.DCM (19.1mg, 0.0234 mmol) in dioxane (2.5 mL) and water (1 mL). Purification byflash column chromatography (DCM to EtOAc with 2% MeOH throughout)afforded 15o as a clear oil (8.4 mg, 9% yield). R_(f)=0.73(DCM/EtOAc/MeOH 47.5:47.5:5 v/v/v). ¹H NMR (400 MHz, DMSO-d₆) δ 12.69(br s, 1H), 8.27 (s, 1H), 8.08-8.00 (m, 2H), 7.84-7.76 (m, 2H),7.49-7.42 (m, 2H), 7.23-7.15 (m, 2H), 7.07 (d, J=2.1 Hz, 1H), 3.71 (s,3H), 3.08 (q, J=7.4 Hz, 2H), 1.31 (t, J=7.5 Hz, 3H). ¹³C NMR (151 MHz,DMSO-d₆) δ 165.2, 160.5 (d, J=240.9 Hz), 155.1, 152.9, 142.8, 134.4,130.9, 130.9 (d, J=2.9 Hz), 128.9, 127.9, 127.8 (d, J=3.6 Hz), 126.6 (d,J=4.6 Hz), 126.4, 124.6, 123.7, 123.6, 122.2, 118.0, 110.3, 102.0 (d,J=17.9 Hz), 52.2, 25.0, 14.9. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −135.3. MS(ESI⁺) calculated for [C₂₃H₂₀FN₂O₃]⁺ [M+H]⁺, 391.1; found 391.1.

Methyl2-((5-ethylnaphthalen-2-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoate(15p)

Methyl ester 15p was prepared according to the procedure for 13a usingphenyl bromide 12p (76.7 mg, 0.199 mmol), fluorinated pyrazole 16 (42.2mg, 0.199 mmol), Cs₂CO₃ (195 mg, 0.597 mmol), and Pd(dppf)Cl₂.DCM (16.3mg, 0.0199 mmol) in dioxane (2.5 mL) and water (1 mL). Purification byflash column chromatography (hexanes to EtOAc) afforded 15p as a clearoil (4.8 mg, 6% yield). R_(f)=0.35 (hexanes/EtOAc 50:50 v/v). ¹H NMR(600 MHz, DMSO-d₆) δ 12.69 (br s, 1H), 8.28 (s, 1H), 8.11 (d, J=9.2 Hz,1H), 8.04 (d, J=2.3 Hz, 1H), 7.81 (dd, J=8.5, 2.3 Hz, 1H), 7.65 (d,J=8.2 Hz, 1H), 7.41-7.37 (m, 1H), 7.31 (dd, J=9.1, 2.6 Hz, 1H),7.29-7.26 (m, 2H), 7.20 (d, J=8.5 Hz, 1H), 3.72 (s, 3H), 3.06 (q, J=7.5Hz, 2H), 1.30 (t, J=7.5 Hz, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 165.2,160.5 (d, J=240.8 Hz), 155.0, 153.0, 140.0, 134.5, 130.9 (d, J=3.1 Hz),128.9, 127.9 (d, J=3.6 Hz), 127.8, 126.6 (d, J=6.1 Hz), 126.6, 126.0,125.6, 123.8, 123.7, 122.3, 118.8, 112.9, 102.0 (d, J=17.9 Hz), 52.2,25.3, 15.2. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −135.3. MS (ESI⁺) calculatedfor [C₂₃H₂₀FN₂O₃]⁺ [M+H]⁺, 391.1; found 391.1.

Methyl2-((7-ethylnaphthalen-2-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoate(15q)

Methyl ester 15q was prepared according to the procedure for 13a usingphenyl bromide 12q (90.3 mg, 0.234 mmol), fluorinated pyrazole 16 (49.7mg, 0.234 mmol), Cs₂CO₃ (229 mg, 0.703 mmol), and Pd(dppf)Cl₂.DCM (19.1mg, 0.0234 mmol) in dioxane (2.5 mL) and water (1 mL). Purification byflash column chromatography (DCM to EtOAc) afforded 15q as a clear oil(15.5 mg, 17% yield). R_(f)=0.64 (DCM/EtOAc 50:50 v/v). ¹H NMR (400 MHz,DMSO-d₆) δ 12.69 (br s, 1H), 8.30-8.26 (m, 1H), 8.04 (d, J=2.3 Hz, 1H),7.89 (d, J=8.9 Hz, 1H), 7.85-7.77 (m, 2H), 7.58 (s, 1H), 7.30 (dd,J=8.4, 1.4 Hz, 1H), 7.23-7.16 (m, 3H), 3.71 (s, 3H), 2.72 (q, J=7.5 Hz,2H), 1.23 (t, J=7.6 Hz, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 165.2, 160.5(d, J=240.8 Hz), 155.5, 153.0, 142.2, 134.1, 130.9 (d, J=4.2 Hz), 129.7,128.9, 128.1, 127.9 (d, J=3.7 Hz), 127.6, 126.6 (d, J=4.8 Hz), 125.8,124.7, 123.7, 122.2, 118.2, 111.8, 102.0 (d, J=17.7 Hz), 52.2, 28.3,15.4. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −135.4. MS (ESI⁺) calculated for[C₂₃H₂₀FN₂O₃]⁺ [M+H]⁺, 391.1; found 391.1.

Methyl2-((4-cyclopropylnaphthalen-2-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoate(15r)

Methyl ester 15r was prepared according to the procedure for 13a usingphenyl bromide 12r (62.0 mg, 0.156 mmol), fluorinated pyrazole 16 (33.1mg, 0.156 mmol), Cs₂CO₃ (153 mg, 0.468 mmol), and Pd(dppf)Cl₂.DCM (12.7mg, 0.0156 mmol) in dioxane (2.5 mL) and water (1 mL). Purification byflash column chromatography (DCM to EtOAc with 2% MeOH throughout)afforded 15r as a white solid (15.5 mg, 25% yield). R_(f)=0.69(DCM/EtOAc/MeOH 47.5:47.5:5 v/v/v). ¹H NMR (400 MHz, DMSO-d₆) δ 12.69(br s, 1H), 8.37-8.31 (m, 1H), 8.27 (app t, J=2.2 Hz, 1H), 8.04 (d,J=2.3 Hz, 1H), 7.83-7.76 (m, 2H), 7.51-7.45 (m, 2H), 7.18 (d, J=8.6 Hz,1H), 7.05 (d, J=2.2 Hz, 1H), 7.03 (d, J=1.9 Hz, 1H), 3.70 (s, 3H),2.49-2.39 (m, 1H), 1.11-1.03 (m, 2H), 0.77-0.71 (m, 2H). ¹³C NMR (101MHz, DMSO-d₆) δ 165.2, 160.5 (d, J=241.1 Hz), 155.1, 152.9, 141.9,134.2, 130.8 (d, J=3.3 Hz), 129.5, 128.9, 127.8 (d, J=3.7 Hz), 127.7,126.6 (d, J=6.8 Hz), 126.5, 124.6, 124.1, 123.7, 122.2, 116.1, 110.2,102.0 (d, J=18.0 Hz), 52.2, 12.7, 6.9. ¹⁹F NMR (376 MHz, DMSO-d₆) δ−135.3. MS (ESI⁺) calculated for [C₂₄H₂₀FN₂O₃]⁺ [M+H]⁺, 403.1; found403.1.

Methyl2-((4-cyclopropyl-7-ethylnaphthalen-2-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoate(15s)

Methyl ester 15s was prepared according to the procedure for 13a usingphenyl bromide 12s (48.0 mg, 0.113 mmol), fluorinated pyrazole 16 (23.9mg, 0.113 mmol), Cs₂CO₃ (110 mg, 0.339 mmol), and Pd(dppf)Cl₂.DCM (9.2mg, 0.011 mmol) in dioxane (2.5 mL) and water (1 mL). Purification byflash column chromatography (DCM to EtOAc) afforded 15s as a clear oil(8.4 mg, 17% yield). R_(f)=0.75 (DCM/EtOAc 50:50 v/v). ¹H NMR (600 MHz,DMSO-d₆) δ 12.69 (br s, 1H), 8.27 (app t, J=2.0 Hz, 1H), 8.24 (d, J=8.6Hz, 1H), 8.03 (d, J=2.3 Hz, 1H), 7.79 (dd, J=8.5, 2.3 Hz, 1H), 7.56 (s,1H), 7.36 (dd, J=8.6, 1.6 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 6.97 (d,J=2.3 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 3.70 (s, 3H), 2.71 (q, J=7.6 Hz,2H), 2.45-2.38 (m, 1H), 1.23 (t, J=7.6 Hz, 3H), 1.08-1.02 (m, 2H),0.75-0.70 (m, 2H). ¹³C NMR (151 MHz, DMSO-d₆) δ 165.3, 160.5 (d, J=240.9Hz), 155.2, 153.0, 142.1, 141.7, 134.4, 130.8 (d, J=3.0 Hz), 128.9,128.0, 127.8 (d, J=3.6 Hz), 126.5 (d, J=4.7 Hz), 125.7, 125.4, 124.1,123.6, 122.1, 115.2, 110.0, 102.1 (d, J=17.9 Hz), 52.2, 28.2, 15.4,12.7, 7.0. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −135.3. MS (ESI⁺) calculated for[C₂₆H₂₄FN₂O₃]⁺ [M+H]⁺, 431.2; found 431.2.

Methyl 2-([1,1′-biphenyl]-4-yloxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoate(15t)

Methyl ester 1St was prepared according to the procedure for 13a usingphenyl bromide 12t (96.3 mg, 0.251 mmol), fluorinated pyrazole 16 (53.3mg, 0.251 mmol), Cs₂CO₃ (246 mg, 0.754 mmol), and Pd(dppf)Cl₂.DCM (20.5mg, 0.0251 mmol) in dioxane (2.5 mL) and water (1 mL). Purification byflash column chromatography (DCM to 30:70 DCM/EtOAc) afforded 1St as abrown solid (23.1 mg, 24% yield). R_(f)=0.68 (DCM/EtOAc 50:50 v/v). ¹HNMR (400 MHz, DMSO-d₆) δ 12.70 (br s, 1H), 8.27 (app t, J=2.0 Hz, 1H),8.02 (d, J=2.3 Hz, 1H), 7.81 (dd, J=8.5, 2.3 Hz, 1H), 7.69-7.61 (m, 4H),7.49-7.41 (m, 2H), 7.38-7.30 (m, 1H), 7.19 (d, J=8.6 Hz, 1H), 7.02 (d,J=8.8 Hz, 2H), 3.75 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 165.2, 160.5(d, J=241.0 Hz), 157.2, 152.9, 139.5, 134.9, 130.9, 130.9 (d, J=3.5 Hz),128.9, 128.2, 127.8 (d, J=3.7 Hz), 127.1, 126.7 (d, J=4.8 Hz), 126.4,123.8, 122.3, 117.8, 102.0 (d, J=18.1 Hz), 52.3. ¹⁹F NMR (376 MHz,DMSO-d₆) δ −135.4. MS (ESI⁺) calculated for [C₂₃H₁₈FN₂O₃]⁺ [M+H]⁺,389.1; found 389.1.

Methyl 2-([1,1′-biphenyl]-3-yloxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoate(15u)

Methyl ester 15u was prepared according to the procedure for 13a usingphenyl bromide 12u (111 mg, 0.289 mmol), fluorinated pyrazole 16 (61.2mg, 0.289 mmol), Cs₂CO₃ (282 mg, 0.867 mmol), and Pd(dppf)Cl₂.DCM (20.5mg, 0.0289 mmol) in dioxane (2.5 mL) and water (1 mL). Purification byflash column chromatography (DCM to 30:70 DCM/EtOAc) afforded 15u as acream-colored solid (19.8 mg, 17% yield). R_(f)=0.73 (DCM/EtOAc 50:50v/v). ¹H NMR (400 MHz, DMSO-d₆) δ 12.69 (br s, 1H), 8.26 (app t, J=1.9Hz, 1H), 8.02 (d, J=2.3 Hz, 1H), 7.79 (dd, J=8.5, 2.3 Hz, 1H), 7.63 (d,J=7.4 Hz, 2H), 7.49-7.33 (m, 5H), 7.23 (app t, J=2.0 Hz, 1H), 7.19 (d,J=8.6 Hz, 1H), 6.95-6.90 (m, 1H), 3.74 (s, 3H). ¹³C NMR (101 MHz,DMSO-d₆) δ 165.3, 160.5 (d, J=241.1 Hz), 157.9, 152.9, 142.1, 139.4,130.8 (d, J=3.3 Hz), 130.5, 129.0, 128.9 (d, J=4.0 Hz), 127.8, 127.8 (d,J=3.8 Hz), 126.7, 123.7, 122.0, 121.5, 117.8, 116.5, 115.7, 102.0 (d,J=17.8 Hz), 52.3. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −135.3. MS (ESI⁺)calculated for [C₂₃H₁₈FN₂O₃]⁺ [M+H]⁺, 389.1; found 389.1.

Methyl2-((3′,5′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoate(15v)

Methyl ester 15v was prepared according to the procedure for 13a usingphenyl bromide 12v (55.0 mg, 0.134 mmol), fluorinated pyrazole 16 (28.4mg, 0.134 mmol), Cs₂CO₃ (131 mg, 0.401 mmol), and Pd(dppf)Cl₂.DCM (10.9mg, 0.0134 mmol) in dioxane (2.5 mL) and water (1 mL). Purification byflash column chromatography (DCM to 50:50 DCM/EtOAc) afforded 15v as anorange solid (10.1 mg, 18% yield). R_(f)=0.73 (DCM/EtOAc 50:50 v/v). ¹HNMR (400 MHz, DMSO-d₆) δ 12.67 (br s, 1H), 8.25 (app t, J=1.7 Hz, 1H),8.00 (d, J=2.2 Hz, 1H), 7.78 (dd, J=8.6, 2.3 Hz, 1H), 7.43 (app t, J=7.8Hz, 1H), 7.40-7.36 (m, 1H), 7.26-7.20 (m, 3H), 7.14 (d, J=8.6 Hz, 1H),7.00 (s, 1H), 6.92-6.87 (m, 1H), 3.75 (s, 3H), 2.31 (s, 6H). ¹³C NMR(101 MHz, DMSO-d₆) δ 165.3, 160.5 (d, J=240.8 Hz), 157.6, 153.1, 142.4,139.3, 138.0, 130.8 (d, J=3.1 Hz), 130.4, 129.2, 128.8, 127.7 (d, J=3.7Hz), 127.7, 126.3 (d, J=4.7 Hz), 124.5, 123.5, 121.6, 116.4, 116.0,102.0 (d, J=17.9 Hz), 52.2, 21.0. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −135.4.MS (ESI⁺) calculated for [C₂₅H₂₂FN₂O₃]⁺ [M+H]⁺, 417.2; found 417.1.

Methyl2-((4′-ethoxy-[1,1′-biphenyl]-3-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoate(15w)

Methyl ester 15w was prepared according to the procedure for 13a usingphenyl bromide 12w (79.8 mg, 0.187 mmol), fluorinated pyrazole 16 (39.6mg, 0.187 mmol), Cs₂CO₃ (183 mg, 0.560 mmol), and Pd(dppf)Cl₂.DCM (15.3mg, 0.0187 mmol) in dioxane (2.5 mL) and water (1 mL). Purification byflash column chromatography (DCM to EtOAc) afforded 15w as acream-colored solid (16.0 mg, 20% yield). R_(f)=0.75 (DCM/EtOAc 50:50v/v). ¹H NMR (600 MHz, DMSO-d₆) δ 12.68 (br s, 1H), 8.26 (app t, J=1.9Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.79 (dd, J=8.5, 2.4 Hz, 1H), 7.55 (d,J=8.8 Hz, 2H), 7.41 (app t, J=7.9 Hz, 1H), 7.38-7.34 (m, 1H), 7.18-7.15(m, 2H), 6.98 (d, J=8.8 Hz, 2H), 6.86 (dd, J=8.0, 2.4 Hz, 1H), 4.05 (q,J=7.0 Hz, 2H), 3.74 (s, 3H), 1.33 (t, J=7.0 Hz, 3H). ¹³C NMR (151 MHz,DMSO-d₆) δ 165.3, 160.5 (d, J=240.9 Hz), 158.4, 157.9, 153.0, 141.8,131.5, 130.8 (d, J=3.0 Hz), 130.4, 128.9, 127.8, 127.7 (d, J=3.6 Hz),126.4 (d, J=4.6 Hz), 123.7, 121.9, 121.0, 115.8, 115.2, 114.8, 102.0 (d,J=17.9 Hz), 63.1, 52.2, 14.6. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −135.3. MS(ESI⁺) calculated for [C₂₅H₂₂FN₂O₄]⁺ [M+H]⁺, 433.2; found 433.2.

Methyl5-(3-fluoro-1H-pyrazol-4-yl)-2-((4′-(3-morpholinopropoxy)-[1,1′-biphenyl]-3-yl)oxy)benzoate(15x)

Methyl ester 15x was prepared according to the procedure for 13a usingphenyl bromide 12x (91.5 mg, 0.174 mmol), fluorinated pyrazole 16 (36.9mg, 0.174 mmol), Cs₂CO₃ (170 mg, 0.521 mmol), and Pd(dppf)Cl₂.DCM (14.2mg, 0.0174 mmol) in dioxane (2.5 mL) and water (1 mL). Purification byflash column chromatography (DCM to EtOAc with 2% MeOH throughout)afforded 15x as a clear oil (21.4 mg, 23% yield). R_(f)=0.20(DCM/EtOAc/MeOH 47.5:47.5:5 v/v/v). ¹H NMR (600 MHz, DMSO-d₆) δ 12.71(br s, 1H), 8.26 (s, 1H), 8.00 (d, J=2.3 Hz, 1H), 7.78 (dd, J=8.5, 2.3Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.41 (app t, J=7.9 Hz, 1H), 7.39-7.34(m, 1H), 7.20-7.14 (m, 2H), 6.99 (d, J=8.8 Hz, 2H), 6.88-6.83 (m, 1H),4.03 (t, J=7.0 Hz, 2H), 3.74 (s, 3H), 3.57 (t, J=4.5 Hz, 4H), 2.41 (t,J=7.2 Hz, 2H), 2.36 (app s, 4H), 1.88 (app quint, J=6.5 Hz, 2H). ¹³C NMR(151 MHz, DMSO-d₆) δ 165.3, 160.5 (d, J=240.9 Hz), 158.5, 157.9, 153.0,141.8, 131.6, 130.8 (d, J=3.1 Hz), 130.4, 128.9, 127.8, 127.7 (d, J=3.5Hz), 126.4 (d, J=4.6 Hz), 123.7, 121.9, 121.0, 115.8, 115.2, 114.9,102.0 (d, J=18.0 Hz), 66.2, 65.9, 54.8, 53.4, 52.2, 25.9. ¹⁹F NMR (376MHz, DMSO-d₆) δ −135.4. MS (ESI⁺) calculated for [C₃₀H₃₁FN₃O₅]⁺ [M+H]⁺,532.2; found 532.2.

Synthesis of 6a-c, 7a, 7b, 8a-g, and 8j-15x4-(1H-pyrazol-4-yl)-[1,1′-biphenyl]-2-carboxylic acid (6a)

A suspension of methyl ester 13a (17.3 mg, 0.0622 mmol) in EtOH (1.5 mL)and 20% (wt/wt) aqueous NaOH (1.5 mL) was stirred at room temperaturefor 48 hours. The reaction mixture was acidified to pH=1 with 1N HCl,diluted with EtOAc (50 mL), and washed with brine (50 mL). The organicphase was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. Purification by flash column chromatography (DCM to 99:1EtOAc/TFA) afforded 6a as a pale yellow solid (16.4 mg, 99% yield).R_(f)=0.10 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (400 MHz, DMSO-d₆)δ 8.19 (s, 2H), 7.90 (s, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.45-7.31 (m, 6H).¹³C NMR (101 MHz, DMSO-d₆) δ 169.9, 140.6, 137.9, 133.1, 132.0, 130.9,128.2, 128.2, 127.2, 127.1, 125.2. HRMS (ESI⁺) calculated for[C₁₆H₁₃N₂O₂]⁺ [M+H]⁺, 265.0977; found 265.0978.

2-(Naphthalen-1-yl)-5-(1H-pyrazol-4-yl)benzoic acid (6b)

Carboxylic acid 6b was prepared according to the procedure for 6a usingmethyl ester 13b (20.8 mg, 0.0633 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 6b as a peach-colored solid (19.9 mg, 99%yield). R_(f)=0.12 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (400 MHz,DMSO-d₆) δ 8.23 (s, 2H), 8.11 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.90 (appt, J=9.2 Hz, 2H), 7.58-7.38 (m, 4H), 7.33 (app d, J=7.0 Hz, 2H). ¹³C NMR(101 MHz, DMSO-d₆) δ 168.5, 139.4, 137.2, 133.4, 133.0, 132.5, 132.1,131.6, 128.1, 127.7, 127.2, 126.1, 126.0, 125.7, 125.6, 125.3, 125.3.HRMS (ESI⁺) calculated for [C₂₀H₁₅N₂O₂]⁺ [M+H]⁺, 315.1132; found315.1134.

2-(Naphthalen-2-yl)-5-(1H-pyrazol-4-yl)benzoic acid (6c)

Carboxylic acid 6c was prepared according to the procedure for 6a usingmethyl ester 13c (22.0 mg, 0.0670 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 6c as a light brown solid (21.1 mg, 99%yield). R_(f)=0.13 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (400 MHz,DMSO-d₆) δ 8.22 (s, 2H), 8.02-7.82 (m, 6H), 7.59-7.46 (m, 4H). ¹³C NMR(101 MHz, DMSO-d₆) δ 169.8, 138.4, 138.1, 133.1, 132.9, 132.2, 132.0,131.3, 131.2, 128.0, 127.5, 127.3, 127.1, 126.5, 126.3, 126.0, 125.5.HRMS (ESI⁺) calculated for [C₂₀H₁₅N₂O₂]⁺ [M+H]⁺, 315.1132; found315.1125.

2-(Phenylamino)-5-(1H-pyrazol-4-yl)benzoic acid (7a)

Carboxylic acid 7a was prepared according to the procedure for 6a usingmethyl ester 14a (28.0 mg, 0.0955 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 7a as a mustard yellow solid (26.6 mg, 99%yield). R_(f)=0.12 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (400 MHz,DMSO-d₆) δ 9.54 (br s, 1H), 8.08 (d, J=2.1 Hz, 1H), 7.98 (s, 2H), 7.65(dd, J=8.7, 2.1 Hz, 1H), 7.35 (t, J=7.8 Hz, 2H), 7.30-7.21 (m, 3H), 7.05(t, J=7.3 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ 169.9, 144.8, 140.8,131.3, 129.5, 127.9, 122.8, 122.6, 120.9, 114.7, 113.3. HRMS (ESI⁺)calculated for [C₁₆H₁₄N₃O₂]⁺ [M+H]⁺, 280.1086; found 280.1083.

2-(Methyl(naphthalen-2-yl)amino)-5-(1H-pyrazol-4-yl)benzoic acid (7b)

Carboxylic acid 7b was prepared according to the procedure for 6a usingmethyl ester 14b (19.1 mg, 0.0534 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 7b as a yellow solid (5.3 mg, 29% yield).R_(f)=0.19 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (600 MHz, DMSO-d₆)δ 8.16 (s, 2H), 7.98 (d, J=1.5 Hz, 1H), 7.86 (dd, J=8.2, 1.6 Hz, 1H),7.66 (app t, J=9.1 Hz, 2H), 7.60 (d, J=9.0 Hz, 1H), 7.37-7.30 (m, 2H),7.18 (app t, J=7.4 Hz, 1H), 6.97 (d, J=1.8 Hz, 1H), 6.77 (dd, J=9.0, 2.0Hz, 1H), 3.31 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 167.8, 146.8, 144.4,134.6, 131.4, 130.9, 129.9, 129.6, 128.1, 127.3, 127.0, 126.8, 126.2,126.0, 122.0, 117.1, 106.6, 40.4. HRMS (ESI⁺) calculated for[C₂₁H₁₈N₃O₂]⁺ [M+H]⁺, 344.1399; found 344.1399.

2-Phenoxy-5-(1H-pyrazol-4-yl)benzoic acid (8a)

Carboxylic acid 8a was prepared according to the procedure for 6a usingmethyl ester 15a (23.7 mg, 0.0805 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8a as a brown solid (22.6 mg, 99% yield).R_(f)=0.09 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (400 MHz, DMSO-d₆)δ 8.26 (s, 2H), 8.00 (s, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.34 (t, J=7.8 Hz,2H), 7.07 (t, J=7.3 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.91 (d, J=8.0 Hz,2H). ¹³C NMR (101 MHz, DMSO-d₆) δ 166.6, 157.8, 152.4, 130.0, 129.8,127.4, 125.3, 122.6, 121.9, 121.9, 117.2. HRMS (ESI⁺) calculated for[C₁₆H₁₃N₂O₃]⁺ [M+H]⁺, 281.0926; found 281.0932.

5-(1H-Pyrazol-4-yl)-2-(o-tolyloxy)benzoic acid (8b)

Carboxylic acid 8b was prepared according to the procedure for 6a usingmethyl ester 15b (23.2 mg, 0.0752 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8b as a brown solid (15.6 mg, 70% yield).R_(f)=0.24 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (600 MHz, DMSO-d₆)δ 8.11 (s, 2H), 7.98 (app t, J=1.6 Hz, 1H), 7.75-7.71 (m, 1H), 7.29 (d,J=7.4 Hz, 1H), 7.16 (app t, J=7.7 Hz, 1H), 7.04 (app t, J=7.4 Hz, 1H),6.84 (dd, J=8.5, 1.4 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 2.22 (s, 3H). ¹³CNMR (151 MHz, DMSO-d₆) δ 166.7, 155.1, 153.2, 131.3, 129.8, 128.3,128.1, 127.4, 127.2, 124.2, 123.3, 119.9, 117.3, 15.8. HRMS (ESI⁺)calculated for [C₁₇H₁₅N₂O₃]⁺ [M+H]⁺, 295.1083; found 295.1088.

5-(1H-Pyrazol-4-yl)-2-(m-tolyloxy)benzoic acid (8c)

Carboxylic acid 8c was prepared according to the procedure for 6a usingmethyl ester 15c (24.5 mg, 0.0795 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8c as a brown solid (16.7 mg, 71% yield).R_(f)=0.25 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (400 MHz, DMSO-d₆)δ 8.14 (s, 2H), 7.99 (s, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.22 (app t, J=7.0Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.89 (d, J=7.1 Hz, 1H), 6.74 (s, 1H),6.69 (d, J=8.2 Hz, 1H), 2.27 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ166.6, 157.8, 152.5, 139.4, 129.9, 129.5, 129.1, 127.3, 125.3, 123.3,121.8, 117.8, 114.3, 21.0. HRMS (ESI⁺) calculated for [C₁₇H₁₅N₂O₃]⁺[M+H]⁺, 295.1083; found 295.1078.

5-(1H-Pyrazol-4-yl)-2-(p-tolyloxy)benzoic acid (8d)

Carboxylic acid 8d was prepared according to the procedure for 6a usingmethyl ester 15d (19.5 mg, 0.0632 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8d as a brown solid (18.4 mg, 99% yield).R_(f)=0.25 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (400 MHz, DMSO-d₆)δ 8.16 (s, 2H), 7.97 (s, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.15 (d, J=7.9 Hz,2H), 6.95 (d, J=8.4 Hz, 1H), 6.82 (d, J=8.0 Hz, 2H), 2.26 (s, 3H). ¹³CNMR (151 MHz, DMSO-d₆) δ 166.7, 155.4, 152.9, 131.7, 130.2, 129.8,128.8, 127.3, 125.0, 121.2, 117.5, 20.2. HRMS (ESI⁺) calculated for[C₁₇H₁₅N₂O₃]⁺ [M+H]⁺, 295.1083; found 295.1082.

2-(3-Fluorophenoxy)-5-(1H-pyrazol-4-yl)benzoic acid (8e)

Carboxylic acid 8e was prepared according to the procedure for 6a usingmethyl ester 15e (14.0 mg, 0.045 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8e as a brown solid (13.4 mg, 99% yield).R_(f)=0.24 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (600 MHz, DMSO-d₆)δ 8.20 (s, 2H), 8.03 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.35 (app q, J=7.1Hz, 1H), 7.14 (d, J=7.8 Hz, 1H), 6.89 (app t, J=7.6 Hz, 1H), 6.74 (d,J=10.4 Hz, 1H), 6.69 (d, J=7.8 Hz, 1H). ¹³C NMR (151 MHz, DMSO-d₆) δ166.3, 162.8 (d, J=243.8 Hz), 159.5 (d, J=10.9 Hz), 151.4, 131.1, 131.0(d, J=9.9 Hz), 127.5, 125.5, 122.7, 112.6 (d, J=2.7 Hz), 109.6, 109.1(d, J=21.0 Hz), 104.4 (d, J=25.0 Hz). HRMS (ESI⁺) calculated for[C₁₆H₁₂FN₂O₃]⁺ [M+H]⁺, 299.0832; found 299.0833.

2-(4-Fluorophenoxy)-5-(1H-pyrazol-4-yl)benzoic acid (8f)

Carboxylic acid 8f was prepared according to the procedure for 6a usingmethyl ester 15f (19.0 mg, 0.0608 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8f as a brown solid (18.1 mg, 99% yield).R_(f)=0.19 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (600 MHz, DMSO-d₆)δ 8.11 (s, 2H), 7.99 (d, J=2.2 Hz, 1H), 7.78 (dd, J=8.5, 2.2 Hz, 1H),7.18 (app t, J=8.7 Hz, 2H), 7.01 (d, J=8.5 Hz, 1H), 6.97-6.93 (m, 2H).¹³C NMR (151 MHz, DMSO-d₆) δ 166.6, 157.7 (d, J=238.3 Hz), 153.9 (d,J=1.7 Hz), 152.7, 129.9, 129.2, 127.4, 125.1, 121.5, 119.0 (d, J=8.4Hz), 116.3 (d, J=23.3 Hz). HRMS (ESI⁺) calculated for [C₁₆H₁₂FN₂O₃]⁺[M+H]⁺, 299.0832; found 299.0836.

2-(Naphthalen-2-yloxy)-5-(1H-pyrazol-4-yl)benzoic acid (8g)

Carboxylic acid 8g was prepared according to the procedure for 6a usingmethyl ester 15g (9.8 mg, 0.029 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8g as a brown solid (9.4 mg, 99% yield).R_(f)=0.14 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (400 MHz, DMSO-d₆)δ 8.16 (s, 2H), 8.05 (d, J=1.1 Hz, 1H), 7.93 (d, J=8.9 Hz, 1H), 7.89 (d,J=7.9 Hz, 1H), 7.84 (dd, J=8.9, 1.1 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H),7.45 (app t, J=7.6 Hz, 1H), 7.40 (app t, J=6.9 Hz, 1H), 7.28 (dd, J=8.9,1.8 Hz, 1H), 7.18 (d, J=1.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H). ¹³C NMR(101 MHz, DMSO-d₆) δ 166.6, 156.0, 152.2, 133.9, 130.1, 129.9, 129.6,129.3, 127.6, 127.5, 126.9, 126.6, 125.4, 124.5, 122.4, 119.0, 111.3.HRMS (ESI⁺) calculated for [C₂₀H₁₅N₂O₃]⁺ [M+H]⁺, 331.1083; found331.1082.

2-(Phenanthren-9-yloxy)-5-(1H-pyrazol-4-yl)benzoic acid (8j)

Carboxylic acid 8j was prepared according to the procedure for 6a usingmethyl ester 15j (9.0 mg, 0.023 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8j as a light brown solid (8.4 mg, 97%yield). R_(f)=0.26 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (600 MHz,DMSO-d₆) δ 8.89 (d, J=8.3 Hz, 1H), 8.79 (d, J=8.1 Hz, 1H), 8.38 (d,J=8.0 Hz, 1H), 8.18 (s, 2H), 8.11 (s, 1H), 7.86 (d, J=7.2 Hz, 1H),7.82-7.77 (m, 2H), 7.74 (app t, J=7.4 Hz, 1H), 7.60-7.53 (m, 2H), 7.21(d, J=8.4 Hz, 1H), 6.96 (s, 1H). ¹³C NMR (151 MHz, DMSO-d₆) δ 166.5,152.2, 152.2, 131.8, 131.1, 130.1, 129.7, 127.8, 127.7, 127.7, 127.2,127.0, 126.7, 125.8, 125.4, 125.2, 123.1, 122.8, 122.4, 122.3, 108.3.HRMS (ESI⁺) calculated for [C₂₄H₁₇N₂O₃]⁺ [M+H]⁺, 381.1239; found381.1240.

2-((Adamantan-2-yl)oxy)-5-(1H-pyrazol-4-yl)benzoic acid (8k)

Carboxylic acid 8k was prepared according to the procedure for 6a usingmethyl ester 15k (28.8 mg, 0.0817 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8k as a brown solid (27.7 mg, 99% yield).R_(f)=0.30 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (600 MHz, DMSO-d₆)δ 8.00 (s, 2H), 7.78 (d, J=2.0 Hz, 1H), 7.64 (dd, J=8.6, 2.0 Hz, 1H),7.12 (d, J=8.7 Hz, 1H), 4.62 (app t, J=3.2 Hz, 1H), 2.16 (d, J=12.0 Hz,2H), 2.08 (s, 2H), 1.87-1.76 (m, 6H), 1.70 (s, 2H), 1.45 (d, J=11.9 Hz,2H). ¹³C NMR (151 MHz, DMSO-d₆) δ 167.8, 153.7, 129.1, 127.0, 124.9,123.3, 115.3, 78.8, 36.9, 35.5, 30.8, 30.8, 26.8, 26.6. HRMS (ESI⁺)calculated for [C₂₀H₂₃N₂O₃]⁺[M+H]⁺, 339.1709; found 339.1706.

2-((1,2-Dihydroacenaphthylen-4-yl)oxy)-5-(1H-pyrazol-4-yl)benzoic acid(8l)

Carboxylic acid 8l was prepared according to the procedure for 6a usingmethyl ester 151 (2.7 mg, 0.0073 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8l as a white solid (2.6 mg, 99% yield).R_(f)=0.21 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (600 MHz, CD₃OD) δ8.12 (s, 1H), 8.06 (s, 2H), 7.76 (d, J=8.4 Hz, 1H), 7.44-7.36 (m, 2H),7.20 (d, J=6.5 Hz, 1H), 7.06-7.03 (m, 2H), 6.97 (s, 1H), 3.42-3.37 (m,4H). ¹³C NMR (151 MHz, CD₃OD) δ 169.1, 159.4, 156.3, 149.7, 146.9,137.3, 133.3, 131.8, 129.8 (2C), 129.5, 125.4, 122.6, 122.6, 119.2,114.1, 109.6, 31.4, 31.0. HRMS (ESI⁺) calculated for [C₂₂H₁₇N₂O₃]⁺[M+H]⁺, 357.1239; found 357.1241.

5-(3-Fluoro-1H-pyrazol-4-yl)-2-(naphthalen-1-yloxy)benzoic acid (8m)

Carboxylic acid 8m was prepared according to the procedure for 6a usingmethyl ester 15m (14.0 mg, 0.0386 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8m as a white solid (10.2 mg, 76% yield).R_(f)=0.29 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (600 MHz, DMSO-d₆)δ 13.01 (br s, 1H), 12.67 (br s, 1H), 8.25 (app t, J=1.8 Hz, 1H), 8.19(d, J=8.0 Hz, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.73(dd, J=8.5, 2.3 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.61-7.54 (m, 2H), 7.42(app t, J=7.9 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.79 (d, J=7.6 Hz, 1H).¹³C NMR (151 MHz, DMSO-d₆) δ 166.4, 160.5 (d, J=240.7 Hz), 153.3, 153.1,134.5, 130.4 (d, J=2.9 Hz), 128.8, 128.1 (d, J=3.5 Hz), 127.7, 126.8,126.3 (d, J=4.6 Hz), 126.1, 126.1, 125.5, 124.7, 122.7, 121.6, 121.3,111.5, 102.2 (d, J=17.9 Hz). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −135.5. HRMS(ESI⁺) calculated for [C₂₀H₁₄FN₂O₃]⁺ [M+H]⁺, 349.0988; found 349.0987.

5-(3-Fluoro-1H-pyrazol-4-yl)-2-(naphthalen-2-yloxy)benzoic acid (8n)

Carboxylic acid 8n was prepared according to the procedure for 6a usingmethyl ester 15n (10.5 mg, 0.0290 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8n as a white solid (8.1 mg, 80% yield).R_(f)=0.21 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹1-1NMR (600 MHz, DMSO-d₆)δ 13.01 (br s, 1H), 12.69 (br s, 1H), 8.28 (s, 1H), 8.05 (d, J=2.1 Hz,1H), 7.94 (d, J=8.9 Hz, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.79 (app d, J=8.3Hz, 2H), 7.46 (app t, J=7.5 Hz, 1H), 7.41 (app t, J=7.5 Hz, 1H), 7.29(dd, J=8.9, 2.4 Hz, 1H), 7.21 (s, 1H), 7.19 (d, J=8.5 Hz, 1H). ¹³C NMR(151 MHz, DMSO-d₆) δ 166.3, 160.5 (d, J=240.7 Hz), 155.7, 152.7, 133.9,130.4 (d, J=3.2 Hz), 129.9, 129.4, 128.9, 128.0 (d, J=4.1 Hz), 127.6,127.0, 126.7 (d, J=4.8 Hz), 126.6, 125.2, 124.6, 122.5, 119.1, 111.6,102.2 (d, J=18.2 Hz). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −135.4. HRMS (ESI⁺)calculated for [C₂₀H₁₄FN₂O₃]⁺ [M+H]⁺, 349.0988; found 349.0988.

2-((4-Ethylnaphthalen-2-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoic acid(8o)

Carboxylic acid 8o was prepared according to the procedure for 6a usingmethyl ester 15o (8.1 mg, 0.021 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8o as a white solid (5.6 mg, 72% yield).R_(f)=0.35 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (600 MHz, DMSO-d₆)δ 12.99 (br s, 1H), 12.68 (br s, 1H), 8.27 (s, 1H), 8.07-7.99 (m, 2H),7.81-7.74 (m, 2H), 7.49-7.41 (m, 2H), 7.21-7.15 (m, 2H), 7.03 (s, 1H),3.08 (q, J=7.3 Hz, 2H), 1.30 (t, J=7.4 Hz, 3H). ¹³C NMR (151 MHz,DMSO-d₆) δ 166.4, 160.5 (d, J=240.9 Hz), 155.3, 152.7, 142.7, 134.5,130.4 (d, J=2.9 Hz), 128.8, 127.9 (d, J=3.5 Hz), 127.9, 127.8, 126.5 (d,J=4.6 Hz), 126.3, 125.2, 124.5, 123.6, 122.3, 118.0, 109.9, 102.2 (d,J=17.9 Hz), 25.0, 14.9. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −135.4. HRMS (ESI⁺)calculated for [C₂₂H₁₈FN₂O₃]⁺ [M+H]⁺, 377.1301; found 377.1301.

2-((5-Ethylnaphthalen-2-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoic acid(8p)

Carboxylic acid 8p was prepared according to the procedure for 6a usingmethyl ester 15p (4.5 mg, 0.012 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8p as a white solid (4.3 mg, 99% yield).R_(f)=0.31 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (600 MHz, DMSO-d₆)δ 13.06 (br s, 1H), 12.68 (br s, 1H), 8.28 (s, 1H), 8.10 (d, J=9.2 Hz,1H), 8.04 (s, 1H), 7.78 (d, J=9.7 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.38(app t, J=7.6 Hz, 1H), 7.29 (dd, J=9.2, 2.0 Hz, 1H), 7.27 (d, J=7.0 Hz,1H), 7.23 (s, 1H), 7.18 (d, J=8.5 Hz, 1H), 3.05 (q, J=7.5 Hz, 2H), 1.30(t, J=7.5 Hz, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 166.4, 160.5 (d, J=240.9Hz), 155.3, 152.7, 140.0, 134.5, 130.4 (d, J=3.1 Hz), 128.9, 128.0 (d,J=3.6 Hz), 127.6, 126.6 (d, J=4.6 Hz), 126.6, 125.9, 125.5, 125.2,123.6, 122.4, 118.8, 112.5, 102.2 (d, J=17.9 Hz), 25.2, 15.2. ¹⁹F NMR(376 MHz, DMSO-d₆) δ −135.4. HRMS (ESI⁺) calculated for [C₂₂H₁₈FN₂O₃]⁺[M+H]⁺, 377.1301; found 377.1301.

2-((7-Ethylnaphthalen-2-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoic acid(8q)

Carboxylic acid 8q was prepared according to the procedure for 6a usingmethyl ester 15q (15.5 mg, 0.0397 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8q as a white solid (10.8 mg, 72% yield).R_(f)=0.35 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (600 MHz, DMSO-d₆)δ 13.00 (br s, 1H), 12.68 (br s, 1H), 8.27 (s, 1H), 8.04 (d, J=2.2 Hz,1H), 7.88 (d, J=8.9 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.77 (dd, J=8.5,2.2 Hz, 1H), 7.57 (s, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.20 (dd, J=8.9, 2.4Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 2.72 (q, J=7.6Hz, 2H), 1.23 (t, J=7.6 Hz, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 166.4,160.5 (d, J=240.8 Hz), 155.8, 152.8, 142.2, 134.1, 130.4 (d, J=2.9 Hz),129.6, 128.8, 128.0 (d, J=3.9 Hz), 127.9, 127.5, 126.6 (d, J=4.6 Hz),125.7, 125.2, 124.6, 122.3, 118.2, 111.5, 102.2 (d, J=17.9 Hz), 28.3,15.4. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −135.4. HRMS (ESI⁺) calculated for[C₂₂H₁₈FN₂O₃]⁺ [M+H]⁺, 377.1301; found 377.1310.

2-((4-Cyclopropylnaphthalen-2-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoicacid (8r)

Carboxylic acid 8r was prepared according to the procedure for 6a usingmethyl ester 15r (15.1 mg, 0.0374 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8r as a sand-colored solid (12.7 mg, 87%yield). R_(f)=0.21 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (600 MHz,DMSO-d₆) δ 12.98 (br s, 1H), 12.67 (br s, 1H), 8.35-8.31 (m, 1H), 8.27(app t, J=1.8 Hz, 1H), 8.03 (d, J=2.3 Hz, 1H), 7.80-7.75 (m, 2H),7.50-7.45 (m, 2H), 7.16 (d, J=8.5 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 7.00(d, J=2.2 Hz, 1H), 2.47-2.40 (m, 1H), 1.10-1.04 (m, 2H), 0.75-0.72 (m,2H). ¹³C NMR (151 MHz, DMSO-d₆) δ 166.4, 160.5 (d, J=240.8 Hz), 155.4,152.7, 141.7, 134.2, 130.4 (d, J=3.0 Hz), 129.4, 128.8, 127.9 (d, J=3.5Hz), 127.7, 126.6 (d, J=4.6 Hz), 126.5, 125.2, 124.5, 124.1, 122.3,116.2, 109.8, 102.2 (d, J=17.8 Hz), 12.8, 6.9. ¹⁹F NMR (376 MHz,DMSO-d₆) δ −135.4. HRMS (ESI⁺) calculated for [C₂₃H₁₈FN₂O₃]⁺ [M+H]⁺,389.1301; found 389.1299.

2-((4-Cyclopropyl-7-ethylnaphthalen-2-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoicacid (8s)

Carboxylic acid 8s was prepared according to the procedure for 6a usingmethyl ester 15s (8.4 mg, 0.020 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8s as a white solid (7.3 mg, 90% yield).R_(f)=0.25 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (500 MHz, DMSO-d₆)δ 12.98 (br s, 1H), 12.67 (br s, 1H), 8.26 (s, 1H), 8.24 (d, J=8.6 Hz,1H), 8.03 (d, J=2.1 Hz, 1H), 7.76 (dd, J=8.5, 2.1 Hz, 1H), 7.56 (s, 1H),7.35 (dd, J=8.6, 1.8 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 6.93 (app s, 2H),2.72 (q, J=7.5 Hz, 2H), 2.44-2.37 (m, 1H), 1.23 (t, J=7.5 Hz, 3H),1.08-1.03 (m, 2H), 0.74-0.69 (m, 2H). ¹³C NMR (151 MHz, DMSO-d₆) δ166.4, 160.5 (d, J=241.0 Hz), 155.5, 152.8, 142.0, 141.5, 134.5, 130.3(d, J=2.7 Hz), 128.8, 127.9, 127.9 (d, J=2.5 Hz), 126.5 (d, J=4.7 Hz),125.6, 125.4, 125.2, 124.1, 122.2, 115.3, 109.7, 102.2 (d, J=17.9 Hz),28.2, 15.4, 12.7, 6.9. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −135.4. HRMS (ESI⁺)calculated for [C₂₅H₂₂FN₂O₃]⁺ [M+H]⁺, 417.1614; found 417.1614.

2-([1,1′-Biphenyl]-4-yloxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoic acid(8t)

Carboxylic acid 8t was prepared according to the procedure for 6a usingmethyl ester 1St (22.8 mg, 0.0587 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8t as a white solid (18.1 mg, 82% yield).R_(f)=0.25 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (600 MHz, DMSO-d₆)δ 13.04 (br s, 1H), 12.67 (br s, 1H), 8.27 (s, 1H), 8.02 (d, J=1.8 Hz,1H), 7.78 (dd, J=8.5, 1.9 Hz, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.63 (d,J=8.2 Hz, 2H), 7.45 (t, J=7.6 Hz, 2H), 7.33 (t, J=7.3 Hz, 1H), 7.17 (d,J=8.5 Hz, 1H), 6.99 (d, J=8.5 Hz, 2H). ¹³C NMR (151 MHz, DMSO-d₆) δ166.3, 160.5 (d, J=240.9 Hz), 157.5, 152.6, 139.6, 134.7, 130.4 (d,J=3.3 Hz), 128.9, 128.9, 128.1, 127.9 (d, J=3.8 Hz), 127.1, 126.7 (d,J=4.5 Hz), 126.4, 125.3, 122.4, 117.5, 102.1 (d, J=17.8 Hz). ¹⁹F NMR(376 MHz, DMSO-d₆) δ −135.4. HRMS (ESI⁺) calculated for [C₂₂H₁₆FN₂O₃]⁺[M+H]⁺, 375.1145; found 375.1145.

2-([1,1′-Biphenyl]-3-yloxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoic acid(8u)

Carboxylic acid 8u was prepared according to the procedure for 6a usingmethyl ester 15u (14.0 mg, 0.0360 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8u as a white solid (9.9 mg, 73% yield).R_(f)=0.36 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (600 MHz, DMSO-d₆)δ 13.03 (br s, 1H), 12.67 (br s, 1H), 8.26 (s, 1H), 8.01 (d, J=1.9 Hz,1H), 7.76 (dd, J=8.4, 1.7 Hz, 1H), 7.62 (d, J=8.2 Hz, 2H), 7.47-7.42 (m,3H), 7.41-7.34 (m, 2H), 7.20 (s, 1H), 7.16 (d, J=8.5 Hz, 1H), 6.90 (d,J=7.3 Hz, 1H). ¹³C NMR (151 MHz, DMSO-d₆) δ 166.4, 160.5 (d, J=239.9Hz), 158.2, 152.7, 142.0, 139.5, 130.4, 130.3 (d, J=2.8 Hz), 129.0,128.8, 127.8 (d, J=2.8 Hz), 127.8, 126.7, 126.5 (d, J=4.9 Hz), 125.3,122.1, 121.2, 116.3, 115.5, 102.1 (d, J=17.9 Hz). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −135.4. HRMS (ESI⁺) calculated for [C₂₂H₁₆FN₂O₃]⁺ [M+H]⁺,375.1145; found 375.1146.

2-((3′,5′-Dimethyl-[1,1′-biphenyl]-3-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoicacid (8v)

Carboxylic acid 8v was prepared according to the procedure for 6a usingmethyl ester 15v (10.0 mg, 0.0240 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8v as a white solid (9.7 mg, 99% yield).R_(f)=0.34 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (600 MHz, DMSO-d₆)δ 13.04 (br s, 1H), 12.67 (br s, 1H), 8.25 (s, 1H), 8.01 (d, J=2.0 Hz,1H), 7.75 (dd, J=8.5, 2.0 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.36 (d,J=7.7 Hz, 1H), 7.22 (s, 2H), 7.20 (s, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.00(s, 1H), 6.87 (dd, J=8.0, 2.2 Hz, 1H), 2.31 (s, 6H). ¹³C NMR (151 MHz,DMSO-d₆) δ 166.4, 160.5 (d, J=240.8 Hz), 157.9, 152.9, 142.3, 139.4,138.0, 130.3, 130.3 (d, J=2.9 Hz), 129.2, 128.8, 127.8 (d, J=3.2 Hz),126.3 (d, J=4.5 Hz), 125.1, 124.5, 121.8, 121.3, 116.2, 115.8, 102.1 (d,J=17.9 Hz), 21.0. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −135.4. HRMS (ESI⁺)calculated for [C₂₄H₂₀FN₂O₃]⁺ [M+H]⁺, 403.1458; found 403.1463.

2-((4′-Ethoxy-[1,1′-biphenyl]-3-yl)oxy)-5-(3-fluoro-1H-pyrazol-4-yl)benzoicacid (8w)

Carboxylic acid 8w was prepared according to the procedure for 6a usingmethyl ester 15w (16.0 mg, 0.0370 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). Purification by flash column chromatography (DCMto 99:1 EtOAc/TFA) afforded 8w as a white solid (14.2 mg, 92% yield).R_(f)=0.25 (DCM/EtOAc/TFA 49.5:49.5:1 v/v/v). ¹H NMR (600 MHz, DMSO-d₆)δ 13.04 (br s, 1H), 12.66 (br s, 1H), 8.26 (s, 1H), 8.01 (d, J=1.8 Hz,1H), 7.75 (dd, J=8.4, 1.7 Hz, 1H), 7.54 (d, J=8.5 Hz, 2H), 7.39 (app t,J=7.9 Hz, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.16-7.13 (m, 2H), 6.99 (d, J=8.6Hz, 2H), 6.83 (d, J=9.1 Hz, 1H), 4.05 (q, J=6.9 Hz, 2H), 1.33 (t, J=6.9Hz, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 166.4, 160.5 (d, J=241.2 Hz),158.4, 158.2, 152.8, 141.7, 131.6, 130.3, 130.3 (d, J=3.5 Hz), 128.8,127.8 (d, J=4.1 Hz), 127.8, 126.4 (d, J=4.6 Hz), 125.2, 122.1, 120.7,115.6, 115.0, 114.8, 102.2 (d, J=17.8 Hz), 63.1, 14.7. ¹⁹F NMR (376 MHz,DMSO-d₆) δ −135.4. HRMS (ESI⁺) calculated for [C₂₄H₂₀FN₂O₄]⁺ [M+1-1]⁺,419.1407; found 419.1403.

5-(3-Fluoro-1H-pyrazol-4-yl)-2-((4′-(3-morpholinopropoxy)-[1,1′-biphenyl]-3-yl)oxy)benzoicacid (8x)

Carboxylic acid 8x was prepared according to the procedure for 6a usingmethyl ester 15x (21.0 mg, 0.0395 mmol) in EtOH (1.5 mL) and 20% (wt/wt)aqueous NaOH (1.5 mL). 8x was obtained as a light brown solid (20.2 mg,99% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 12.69 (br s, 1H), 10.76 (br s,1H), 8.26 (s, 1H), 8.01 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.56 (d, J=8.2Hz, 2H), 7.40 (app t, J=7.9 Hz, 1H), 7.34 (d, J=7.5 Hz, 1H), 7.18-7.11(m, 2H), 7.01 (d, J=8.2 Hz, 2H), 6.84 (d, J=7.7 Hz, 1H), 4.08 (t, J=5.8Hz, 2H), 3.87-3.65 (m, 6H), 2.97 (s, 4H), 2.08 (s, 2H). ¹³C NMR (151MHz, DMSO-d₆) δ 166.4, 160.5 (d, J=240.9 Hz), 158.2, 152.8, 141.6,131.9, 130.3, 130.3 (d, J=3.6 Hz), 129.1, 128.8, 128.7, 127.8, 127.8 (d,J=3.5 Hz), 126.4 (d, J=4.8 Hz), 125.2, 122.0, 120.7, 115.6, 115.0, 102.1(d, J=18.1 Hz), 68.3, 65.3, 63.9, 59.8, 29.0. ¹⁹F NMR (376 MHz, DMSO-d₆)δ −135.4. HRMS (ESI⁺) calculated for [C₂₉H₂₉FN₃O₅]⁺ [M+H]⁺, 518.2091;found 518.2097.

Synthesis of 8h 5-Bromo-2-(naphthalen-2-yloxy)aniline (17)

This procedure was adapted from Maiti et al.² To a flame-dried vial wereadded 2-naphthol (400 mg, 2.77 mmol), 5-bromo-2-iodoaniline (992 mg,3.33 mmol), copper (I) iodide (26.4 mg, 0.139 mmol), 2-picolinic acid(34.2 mg, 0.277 mmol), potassium phosphate (1.18 g, 5.55 mmol), andanhydrous DMSO (3.5 mL). The vial was sealed, degassed with N₂ for 7minutes, and heated at 80° C. for 24 hours. The reaction mixture wasdiluted with EtOAc (100 mL) and washed with brine (100 mL). The organicphase was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. Purification by flash column chromatography (hexanes to 90:10hexanes/EtOAc) afforded 17 as a russet-colored solid (292 mg, 33%yield). R_(f)=0.29 (hexanes/EtOAc 90:10 v/v). ¹H NMR (600 MHz, CDCl₃) δ7.84-7.79 (m, 2H), 7.68 (d, J=8.2 Hz, 1H), 7.45 (app t, J=7.5 Hz, 1H),7.39 (app t, J=7.5 Hz, 1H), 7.26 (s, 1H), 7.21 (s, 1H), 7.00 (s, 1H),6.84 (d, J=8.5 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 3.90 (br s, 2H). ¹³C NMR(151 MHz, CDCl₃) δ 155.0, 142.3, 140.3, 134.4, 130.2, 130.2, 127.9,127.2, 126.8, 124.8, 121.8, 121.5, 119.1, 118.9, 117.7, 112.0. MS (ESI⁺)calculated for [C₁₆H₁₃BrNO]⁺ [M+H]⁺, 314.0; found 314.1.

(5-Bromo-2-(naphthalen-2-yloxy)phenyl)(methyl)sulfane (18)

This procedure was adapted from Hanson et al.³ To a mixture of 17 (289mg, 0.921 mmol) and dimethyl disulfide (2.5 mL) under N₂ atmosphere at90° C. was added tert-butyl nitrite (0.18 mL, 1.4 mmol) in fiveequivalent portions over 10 minutes. The contents were stirred for 20minutes at 90° C. before removal of the solvent in vacuo. Purificationby flash column chromatography (hexanes to 90:10 hexanes/EtOAc) afforded18 as a yellow oil (255 mg, 80% yield). R_(f)=0.59 (hexanes/EtOAc 90:10v/v). ¹H NMR (600 MHz, CDCl₃) δ 7.86-7.79 (m, 2H), 7.69 (d, J=8.2 Hz,1H), 7.45 (app t, J=7.5 Hz, 1H), 7.40 (app t, J=7.5 Hz, 1H), 7.36 (s,1H), 7.26-7.21 (m, 3H), 6.81 (d, J=8.5 Hz, 1H), 2.46 (s, 3H). ¹³C NMR(151 MHz, CDCl₃) δ 154.7, 152.5, 134.4, 133.7, 130.4, 130.2, 128.8,128.7, 127.9, 127.3, 126.8, 124.9, 120.9, 119.3, 117.4, 113.2, 14.8.

2-(4-Bromo-2-(methylsulfonyl)phenoxy)naphthalene (19)

This procedure was adapted from Hanson et al.³ To a flask containing 18(83.9 mg, 0.243 mmol) dissolved in acetone (1.5 mL) and water (1.5 mL)cooled to 0° C. was added oxone (179 mg, 0.292 mmol). The contents wereslowly allowed to come to room temperature. After 17 hours, the reactionmixture was diluted with EtOAc (75 mL) and washed with brine (75 mL).The organic phase was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. Purification by flash column chromatography (hexanesto 70:30 hexanes/EtOAc) afforded 19 as a clear oil (14.9 mg, 16% yield).R_(f)=0.43 (hexanes/EtOAc 75:25 v/v). ¹H NMR (400 MHz, CDCl₃) δ 8.22 (d,J=2.4 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.77 (d,J=7.7 Hz, 1H), 7.61 (dd, J=8.7, 2.3 Hz, 1H), 7.55-7.47 (m, 3H), 7.27(dd, J=9.2, 2.3 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 3.36 (s, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 155.1, 152.8, 138.2, 134.3, 132.5, 132.4, 131.3,130.8, 128.0, 127.6, 127.2, 126.0, 120.5, 119.9, 116.7, 115.6, 43.6. MS(ESI⁺) calculated for [C₁₇H₁₄BrO₃S]⁺ [M+H]⁺, 377.0; found 377.0.

4-(3-(Methylsulfonyl)-4-(naphthalen-2-yloxy)phenyl)-1H-pyrazole (8h)

Methyl sulfone 8h was prepared according to the procedure for 13a usingphenyl bromide 19 (14.9 mg, 0.0395 mmol), 4-pyrazoleboronic acid pincolester (7.7 mg, 0.040 mmol), Cs₂CO₃ (38.6 mg, 0.118 mmol), andPd(dppf)Cl₂.DCM (3.2 mg, 0.0040 mmol) in dioxane (1.5 mL) and water (0.6mL). Purification by flash column chromatography (hexanes to EtOAc with2% MeOH throughout) afforded 8h as a white solid (4.4 mg, 30% yield).R_(f)=0.28 (hexanes/EtOAc/MeOH 47.5:47.5:5 v/v/v). ¹H NMR (400 MHz,CDCl₃) δ 8.20 (s, 1H), 7.92-7.85 (m, 4H), 7.77 (d, J=7.9 Hz, 1H), 7.64(d, J=8.4 Hz, 1H), 7.54-7.45 (m, 3H), 7.32 (d, J=8.9 Hz, 1H), 7.00 (d,J=8.5 Hz, 1H), 3.38 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 154.2, 153.4,134.3, 132.3, 131.5, 131.5, 131.4, 131.1, 130.6, 128.4, 128.0, 127.5,127.1, 126.6, 125.7, 120.0, 119.8, 116.2, 43.6. HRMS (ESI⁺) calculatedfor [C₂₀H₁₇N₂O₃S]⁺ [M+H]⁺, 365.0960; found 365.0959.

Synthesis of 8i 5-Bromo-2-hydroxybenzenesulfonamide (20)

To a suspension of 5-bromo-2-methoxybenzenesulfonamide (300 mg, 1.13mmol) in anhydrous DCM (6 mL) cooled to −78° C. was added borontribromide (1M in DCM, 2.0 mL, 2.0 mmol) dropwise. The mixture wasstirred at −78° C. for 1 hour, then at room temperature for 2 hours.After quenching at −78° C. with MeOH (1 mL), the reaction mixture wasdiluted with EtOAc (100 mL) and washed with brine (100 mL). The organicphase was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. Purification by flash column chromatography (DCM to EtOAc)afforded 20 as a white solid (218 mg, 77% yield). R_(f)=0.38 (DCM/EtOAc50:50 v/v). ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (br s, 1H), 7.71 (d, J=2.0Hz, 1H), 7.57 (dd, J=8.7, 2.0 Hz, 1H), 7.12 (br s, 2H), 6.95 (d, J=8.7Hz, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ 154.1, 135.8, 131.3, 129.6, 119.3,108.9. MS (ESI⁺) calculated for [C₆H₇BrNO₃S]⁺ [M+H]⁺, 251.9; found251.9.

5-Bromo-2-(naphthalen-2-yloxy)benzenesulfonamide (21)

Phenyl bromide 21 was prepared according to the procedure for 17 usingphenol 20 (213 mg, 0.846 mmol), 2-iodonaphthalene (181 mg, 0.711 mmol),copper (I) iodide (8.1 mg, 0.042 mmol), 2-picolinic acid (10.4 mg,0.0846 mmol), and potassium phosphate (359 mg, 1.69 mmol) in anhydrousDMSO (2 mL). Purification by flash column chromatography (hexanes toEtOAc) afforded 21 as a fuschia oil (99.2 mg, 37% yield). R_(f)=0.18(hexanes/EtOAc 50:50 v/v). ¹H NMR (400 MHz, DMSO-d₆) δ 11.30 (br s, 1H),10.34 (br s, 1H), 7.82-7.75 (m, 3H), 7.72 (d, J=7.9 Hz, 1H), 7.55-7.53(m, 1H), 7.51 (dd, J=8.8, 2.5 Hz, 1H), 7.43 (app t, J=7.1 Hz, 1H), 7.38(app t, J=7.3 Hz, 1H), 7.34 (dd, J=8.7, 1.8 Hz, 1H), 6.87 (d, J=8.7 Hz,1H). ¹³C NMR (101 MHz, DMSO-d₆) δ 154.8, 137.2, 135.4, 133.2, 131.9,129.8, 128.8, 127.5, 127.0, 126.6, 126.5, 124.9, 120.0, 119.5, 115.2,109.0. MS (ESI⁺) calculated for [C₁₆H₁₃BrNO₃S]⁺ [M+H]⁺, 378.0; found378.0.

2-(Naphthalen-2-yloxy)-5-(1H-pyrazol-4-yl)benzenesulfonamide (8i)

Sulfonamide 8i was prepared according to the procedure for 13a usingphenyl bromide 21 (90.0 mg, 0.238 mmol), 4-pyrazoleboronic acid pincolester (46.2 mg, 0.238 mmol), Cs₂CO₃ (233 mg, 0.714 mmol), andPd(dppf)Cl₂.DCM (19.4 mg, 0.0238 mmol) in dioxane (2.5 mL) and water (1mL). Purification by flash column chromatography (DCM to EtOAc with 2%MeOH throughout) afforded 8i as a white solid (13.1 mg, 15% yield).R_(f)=0.31 (DCM/EtOAc/MeOH 47.5:47.5:5 v/v/v). ¹H NMR (400 MHz, DMSO-d₆)δ 12.89 (br s, 1H), 10.79 (br s, 1H), 10.22 (br s, 1H), 8.10 (s, 1H),7.91 (d, J=2.2 Hz, 1H), 7.78 (s, 1H), 7.76-7.71 (m, 2H), 7.69 (d, J=8.2Hz, 1H), 7.59-7.53 (m, 2H), 7.42-7.30 (m, 3H), 6.88 (d, J=8.5 Hz, 1H).¹³C NMR (151 MHz, DMSO-d₆) δ 153.5, 135.8, 133.2, 131.5, 129.6, 128.6,127.4, 127.0, 126.5, 126.3, 125.0, 124.8, 124.6, 123.8, 119.9, 119.9,117.5, 114.5. HRMS (ESI⁺) calculated for [C₁₉H₁₆N₃O₃S]⁺ [M+H]⁺,366.0912; found 366.0912.

Synthesis of Fluorinated Pyrazole 16

4-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (22)

To a solution of 4-bromopyrazole (4.00 g, 27.2 mmol) in anhydrous THF(25 mL) cooled to 0° C. was added NaH (60% dispersion in mineral oil,1.63 g, 40.8 mmol) in four equivalent portions. The contents werestirred at 0° C. for 30 minutes, and then 2-(trimethylsilyl)ethoxymethylchloride (5.06 mL, 28.6 mmol) was added slowly. The reaction was stirredat room temperature for 16 hours, diluted with diethyl ether (200 mL),and washed with brine (100 mL). The organic phase was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to afford 22 asa clear oil (7.50 g, 99% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.59 (s, 1H),7.49 (s, 1H), 5.38 (s, 2H), 3.55 (t, J=8.1 Hz, 2H), 0.90 (t, J=8.5 Hz,2H), −0.02 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 140.5, 129.6, 94.8, 80.8,67.1, 17.9, −1.3.

4-Bromo-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (23)

This procedure was adapted from Albrecht et al.⁴ To a solution ofbromopyrazole 22 (4.50 g, 16.2 mmol) in anhydrous THF (30 mL) cooled to−78° C. was slowly added lithium diisopropylamide (2M in THF, 12.2 mL,24.3 mmol). The contents were stirred at −78° C. for 1.5 hours, and thenN-fluorobenzenesulfonimide (dissolved in 15 mL anhydrous THF, 7.68 g,24.3 mmol) was added followed by a THF rinse (15 mL). The mixture wasstirred at −78° C. for 1 hour before quenching with saturated NH₄Cl (30mL). The solvent was removed in vacuo, and the residue was dissolved inEtOAc (200 mL) and washed with brine (100 mL). The organic phase wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure.Purification by flash column chromatography (hexanes to 95:5hexanes/EtOAc) afforded 23 as a white solid (814 mg, 17% yield).R_(f)=0.41 (hexanes/EtOAc 90:10 v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.40 (d,J=2.2 Hz, 1H), 5.35 (s, 2H), 3.61 (t, J=8.2 Hz, 2H), 0.91 (t, J=8.2 Hz,2H), −0.01 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 151.4 (d, J=277.4), 139.5(d, J=6.8 Hz), 76.5 (d, J=1.3 Hz), 74.1 (d, J=17.8 Hz), 67.2, 17.6,−1.5. ¹⁹F NMR (376 MHz, DMSO-d₆) δ −136.4.

3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(16)

To a slurry of n-BuLi (2.5 M in hexanes, 3.30 mL, 8.26 mmol) inanhydrous THF (3 mL) cooled to −78° C. was added bromopyrazole 23(dissolved in 4 mL anhydrous THF, 813 mg, 2.75 mmol) dropwise, followedby a THF rinse (4 mL). The contents were stirred for 1 hour at −78° C.,then at room temperature for 2 hours. The reaction was cooled back to−78° C. for the addition of triisopropylborate (0.76 mL, 3.3 mmol),after which, it was returned to room temperature for 3 hours. Pinacol(dissolved in 6 mL anhydrous THF, 439 mg, 3.72 mmol) was added dropwise.After stirring for 15 minutes, the reaction mixture was quenched withglacial AcOH (0.5 mL) and filtered through a plug of celite. Thefiltrate was diluted in EtOAc (100 mL) and washed with brine (100 mL).The organic phase was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. Purification by flash column chromatography (hexanesto 50:50 hexanes/EtOAc) afforded 16 as a pale yellow solid (226 mg, 39%yield). R_(f)=0.45 (hexanes/EtOAc 50:50 v/v). ¹H NMR (500 MHz, DMSO-d₆)δ 12.63 (br s, 1H), 7.84 (s, 1H), 1.25 (s, 12H). ¹³C NMR (126 MHz,DMSO-d₆) δ 156.0 (d, J=244.7), 137.5, 83.0, 24.5. ¹⁹F NMR (470 MHz,DMSO-d₆) δ −128.2. MS (ESI⁺) calculated for [C₉H₁₅BFN₂O₂]⁺ [M+H]⁺,213.1; found 213.1.

Synthesis of Acenaphthyl Intermediate 28

Dimethyl naphthalene-1,8-dicarboxylate (24)

This procedure was adapted from Brown et al.⁵ To a suspension of3-hydroxy-1,8-naphthalic anhydride (5.00 g, 23.3 mmol) in water (20 mL)was added KOH (dissolved in 20 mL water, 4.32 g, 77.0 mmol). Dimethylsulfate (11.1 mL, 117 mmol) was added dropwise, and the mixture wasstirred at room temperature for 6 hours. Additional portions of KOH(dissolved in 100 mL water, 5.63 g, 23.3 mmol) and dimethyl sulfate(11.1 mL, 117 mmol) were added all at once, and the reaction was stirredat room temperature for 18 hours. The reaction mixture was filteredthrough a pad of celite. The filtrate was diluted in diethyl ether (250mL) and washed with brine (100 mL). The organic phase was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to afford 24 asa yellow gel (6.40 g, 99% yield). R_(f)=0.55 (hexanes/EtOAc 50:50 v/v).¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (dd, J=8.2, 0.9 Hz, 1H), 7.77 (dd,J=7.1, 1.1 Hz, 1H), 7.66 (d, J=2.7 Hz, 1H), 7.60 (app t, J=8.1 Hz, 1H),7.55 (d, J=2.7 Hz, 1H), 3.93 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H). ¹³CNMR (101 MHz, DMSO-d₆) δ 168.5, 167.9, 156.1, 135.7, 131.5, 131.0,129.3, 127.5, 126.1, 122.0, 121.7, 110.6, 55.8, 52.2, 52.0. MS (ESI⁺)calculated for [C₁₄H₁₁O₄]⁺ [M−OCH₃]⁺, 243.1; found 243.1.

(3-Methoxynaphthalene-1,8-diyl)dimethanol (25)

This procedure was adapted from Brown et al.⁵ To a suspension of diester24 (6.43 g, 23.4 mmol) in anhydrous diethyl ether (120 mL) and anhydrousbenzene (11 mL) was slowly added lithium aluminium hydride (2.63 g, 70.3mmol). Once frothing subsided, the walls of the flask were washed withmore diethyl ether (15 mL), and the contents were heated at reflux for 5hours and then at room temperature for 16 hours. The reaction wasquenched with water (2 mL), a solution of 5M aqueous NaOH (2 mL), and anadditional portion of water (6 mL). The contents were stirred for 15minutes. A few scoops of MgSO₄ were added, and then the mixture wasstirred for another 15 minutes. The contents were filtered, and thesolid was collected and dried to afford 25 as a white solid (2.95 g, 58%yield). R_(f)=0.32 (hexanes/EtOAc 40:60 v/v). ¹H NMR (600 MHz, DMSO-d₆)δ 7.76 (d, J=7.9 Hz, 1H), 7.43 (d, J=6.5 Hz, 1H), 7.38 (app t, J=7.5 Hz,1H), 7.32 (d, J=2.4 Hz, 1H), 7.25 (d, J=2.5 Hz, 1H), 5.31 (app t, J=5.5Hz, 1H), 5.24 (t, J=5.4 Hz, 1H), 5.08 (d, J=5.5 Hz, 2H), 4.98 (d, J=5.4Hz, 2H), 3.87 (s, 3H). ¹³C NMR (151 MHz, DMSO-d₆) δ 155.9, 140.9, 138.4,136.7, 128.1, 126.0, 125.3, 125.3, 119.3, 106.5, 63.8, 62.9, 55.0. MS(ESI⁺) calculated for [C₁₃H₁₃O₂]⁺ [M-OH]⁺, 201.1; found 201.1.

1,8-Bis(bromomethyl)-3-methoxynaphthalene (26)

This procedure was adapted from Brown et al.⁵ To a suspension of diol 25(2.95 g, 13.5 mmol) and LiBr (705 mg, 8.11 mmol) in anhydrous diethylether (140 mL) under N₂ atmosphere at 0° C. was slowly added phosphorustribromide (3.20 mL, 33.8 mmol). The contents were stirred at roomtemperature for 17 hours, then quenched at 0° C. with water (4 mL). Thereaction mixture was diluted with diethyl ether (250 mL) and washed withbrine (100 mL). The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford 26 as an orange solid(4.56 g, 98% yield). R_(f)=0.66 (hexanes/EtOAc 75:25 v/v). ¹H NMR (400MHz, CDCl₃) δ 7.77 (d, J=7.9 Hz, 1H), 7.49-7.44 (m, 1H), 7.40 (app t,J=7.5 Hz, 1H), 7.29 (s, 1H), 7.18 (s, 1H), 5.25 (s, 2H), 5.23 (s, 2H),3.92 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 156.5, 137.9, 135.2, 133.6,130.9, 130.8, 126.3, 125.2, 124.5, 109.7, 55.5, 37.4, 36.7. MS (ESI⁺)calculated for [C₁₃H₁₃Br₂O]⁺ [M+H]⁺, 342.9; found 342.9.

4-Methoxy-1,2-dihydroacenaphthylene (27)

To a solution of dibromide 26 (678 mg, 1.97 mmol) in anhydrous benzene(40 mL) was added phenyllithium (1.8 M in di-n-butyl ether, 1.20 mL,2.17 mmol) dropwise. The reaction was stirred at room temperature for 1hour and then heated at reflux for 3.5 hours. The solvent was removed invacuo, and the residue was dissolved in EtOAc (100 mL) and washed withbrine (100 mL). The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. Purification by flash columnchromatography (hexanes to 90:10 hexanes/EtOAc) afforded 27 as a yellowsolid (274 mg, 75% yield). R_(f)=0.67 (hexanes/EtOAc 90:10 v/v). ¹H NMR(400 MHz, CDCl₃) δ 7.47 (d, J=8.1 Hz, 1H), 7.40 (app t, J=6.9 Hz, 1H),7.14 (d, J=6.8 Hz, 1H), 6.94 (s, 1H), 6.91 (s, 1H), 3.91 (s, 3H),3.41-3.32 (m, 4H). ¹³C NMR (101 MHz, CDCl₃) δ 160.5, 147.9, 145.7,135.2, 132.2, 128.6, 121.3, 117.3, 112.2, 101.0, 55.7, 30.8, 30.2. MS(ESI⁺) calculated for [C₁₃H₁₃O]⁺ [M+H]⁺, 185.1; found 185.1.

1,2-Dihydroacenaphthylen-4-ol (28)

Alcohol 28 was prepared according to the procedure for 20 using methylether 27 (831 mg, 4.51 mmol) and boron tribromide (1M in DCM, 8.11 mL,8.11 mmol) in anhydrous DCM (31 mL). Purification by flash columnchromatography (hexanes to 75:25 hexanes/EtOAc) afforded 28 as acream-colored solid (534 mg, 70% yield). R_(f)=0.45 (hexanes/EtOAc 75:25v/v). ¹H NMR (600 MHz, CDCl₃) δ 7.43-7.37 (m, 2H), 7.13 (d, J=7.4 Hz,1H), 6.91-6.88 (m, 2H), 4.93 (s, 1H), 3.40-3.37 (m, 2H), 3.36-3.33 (m,2H). ¹³C NMR (151 MHz, CDCl₃) δ 156.0, 148.7, 145.9, 135.1, 132.3,128.8, 121.0, 117.2, 111.3, 104.6, 30.8, 30.3. MS (ESI⁺) calculated for[C₁₂H₁₁O]⁺ [M+H]⁺, 171.1; found 171.1.

Synthesis of Naphthol Intermediates 31o and 31s

2,4-Dibromonaphthalen-1-amine (29o)

This procedure was adapted from MacLean et al.⁶ To a solution of1-naphthylamine (5.00 g, 34.9 mmol) in glacial AcOH (15 mL) cooled to 0°C. was slowly added bromine (dissolved in 25 mL glacial AcOH, 3.96 mL,76.8 mmol). The reaction was stirred at 0° C. for 5 minutes, then at 60°C. for another 15 minutes. The mixture was cooled to room temperature.The precipitate was collected by suction filtration and washed with AcOH(50 mL). The purple solid was suspended in water (70 mL) and stirred,adding NaOH until the solution tested alkaline. The mixture was cooledto 0° C., and the precipitate was collected by filtration and washedwith water until the filtrate ran clear. The solid was air driedovernight to afford 290 as a purple solid (9.47 g, 90% yield). ¹H NMR(400 MHz, CDCl₃) δ 8.17 (d, J=8.9 Hz, 1H), 7.83-7.77 (m, 2H), 7.62-7.57(m, 1H), 7.56-7.50 (m, 1H), 4.65 (br s, 2H). ¹³C NMR (101 MHz, CDCl₃) δ139.7, 132.8, 131.5, 128.2, 127.5, 126.6, 124.5, 121.5, 111.0, 103.5. MS(ESI⁺) calculated for [C₁₀H₈Br₂N]⁺ [M+H]⁺, 301.9; found 301.9.

2,4-dibromo-7-ethylnaphthalen-1-amine (29s)

Dibromide 29s was prepared according to the procedure for 29o usingaminonaphthalene 44 (1.10 g, 6.42 mmol) and bromine (0.73 mL, 14 mmol)in glacial AcOH (28 mL). Purification by filtration afforded 29s as abrown solid (1.80 g, 85% yield). R_(f)=0.38 (hexanes/EtOAc 90:10 v/v).¹H NMR (600 MHz, CDCl₃) δ 8.08 (d, J=8.6 Hz, 1H), 7.73 (s, 1H), 7.56 (s,1H), 7.46 (d, J=8.6 Hz, 1H), 4.61 (br s, 2H), 2.85 (q, J=7.6 Hz, 2H),1.33 (t, J=7.6 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 143.0, 139.3, 131.8,130.0, 128.6, 128.2, 124.8, 119.5, 111.1, 103.7, 29.3, 15.8. MS (ESI⁺)calculated for [C₁₂H₁₂Br₂N]⁺[M+H]⁺, 329.9; found 329.9.

4-bromo-1-diazonionaphthalen-2-olate (30o)

This procedure was adapted from MacLean et al.⁶ To a solution ofdibromide 290 (9.47 g, 31.4 mmol) in glacial AcOH (160 mL) and propionicacid (30 mL) cooled to 0° C. was added NaNO₂ (2.28 g, 31.4 mmol) in fourequivalent portions. The reaction was stirred for 10 minutes. Water (160mL) was added, and the mixture was filtered quickly. The filtrate wasdiluted with more water (1 L), and the product was allowed toprecipitate overnight. Filtration afforded 30o as a brown solid (4.96 g,63% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 7.99 (d, J=8.1 Hz, 1H),7.69-7.63 (m, 2H), 7.45-7.40 (m, 1H), 7.20 (s, 1H). ¹³C NMR (151 MHz,DMSO-d₆) δ 176.0, 137.1, 130.9, 129.3, 129.2, 126.9, 125.3, 123.5,121.3, 78.3. MS (ESI⁺) calculated for [C₁₀H₆BrN₂O]⁺ [M+H]⁺, 249.0; found248.9.

4-bromo-1-diazonio-7-ethylnaphthalen-2-olate (30s)

Zwitterion 30s was prepared according to the procedure for 30o usingdibromide 29s (1.80 g, 5.48 mmol) and NaNO₂ (397 mg, 5.75 mmol) inglacial AcOH (25 mL) and propionic acid (5 mL). Purification byfiltration afforded 30s as a brown solid (1.02 g, 67% yield). R_(f)=0.38(hexanes/EtOAc 90:10 v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J=8.3 Hz,1H), 7.20 (d, J=8.3 Hz, 1H), 7.10 (s, 1H), 7.06 (s, 1H), 2.78 (q, J=7.6Hz, 2H), 1.30 (t, J=7.6 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 166.2,148.0, 138.7, 130.6, 129.1, 126.9, 125.8, 123.2, 118.8, 110.2, 29.1,15.5. MS (ESI⁺) calculated for [C₁₂H₁₀BrN₂O]⁺ [M+H]⁺, 277.0; found277.0.

4-Bromonaphthalen-2-ol (31o)

This procedure was adapted from MacLean et al.⁶ To a suspension ofzwitterion 30o (4.96 g, 19.9 mmol) in EtOH (100 mL) cooled to 0° C. wasslowly added sodium borohydride (791 mg, 20.9 mmol). After 3 hours at 0°C., the mixture was poured into 300 mL of ice water. Once the icemelted, the product was extracted with EtOAc (150 mL). The organic phasewas dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto afford 310 as a black solid (4.37 g, 98% yield). R_(f)=0.46(hexanes/EtOAc 75:25 v/v). ¹H NMR (400 MHz, DMSO-d₆) δ 10.11 (br s, 1H),7.97 (d, J=8.3 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.51-7.45 (m, 2H),7.44-7.38 (m, 1H), 7.20 (d, J=1.7 Hz, 1H). ¹³C NMR (151 MHz, DMSO-d₆) δ155.1, 135.3, 127.2, 126.9, 126.0, 125.8, 124.5, 122.4, 122.2, 109.3. MS(ESI⁺) calculated for [C₁₀H₈BrO]⁺ [M+H]⁺, 223.0; found 223.0.

4-Bromo-7-ethylnaphthalen-2-ol (31s)

Naphthol 31s was prepared according to the procedure for 31o usingzwitterion 30s (1.02 g, 3.68 mmol) and sodium borohydride (146 mg, 3.87mmol) in EtOH (25 mL). Purification by flash column chromatography(hexanes to 75:25 hexanes/EtOAc) afforded 31s as a purple solid (404 mg,44% yield). R_(f)=0.50 (hexanes/EtOAc 75:25 v/v). ¹H NMR (400 MHz,CDCl₃) δ 8.04 (d, J=8.7 Hz, 1H), 7.44 (s, 1H), 7.38 (d, J=2.3 Hz, 1H),7.29 (d, J=8.6 Hz, 1H), 7.07 (d, J=2.1 Hz, 1H), 4.94 (br s, 1H), 2.80(q, J=7.6 Hz, 2H), 1.31 (t, J=7.6 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ153.1, 143.7, 135.6, 127.1, 126.4, 126.3, 124.7, 123.6, 121.1, 109.5,29.0, 15.5. MS (EST) calculated for [C₁₂H₁₀BrO]⁻ [M−H]⁻, 249.0; found249.0.

Synthesis of Naphthol Intermediates 34o-q

1-Bromo-3-methoxynaphthalene (32o)

To a suspension of naphthol 310 (1.77 g, 7.93 mmol) in water (20 mL) atroom temperature was added NaOH (dissolved in 50 mL water, 634 mg, 15.9mmol). The contents were stirred until all solids were dissolved beforethe dropwise addition of dimethyl sulfate (1.50 mL, 15.9 mmol). After 24hours of stirring, the reaction mixture was washed with diethyl ether(125 mL). The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. Purification by flash columnchromatography (hexanes to 90:10 hexanes/EtOAc) afforded 32o as a whitesolid (766 mg, 41% yield). R_(f)=0.48 (hexanes/EtOAc 90:10 v/v). ¹H NMR(400 MHz, CDCl₃) δ 8.14 (d, J=8.1 Hz, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.50(d, J=2.3 Hz, 1H), 7.49-7.41 (m, 2H), 7.12 (d, J=2.1 Hz, 1H), 3.92 (s,3H). ¹³C NMR (101 MHz, CDCl₃) δ 157.3, 135.3, 127.8, 127.3, 127.3,127.1, 125.1, 123.6, 122.8, 106.2, 55.7.

1-Bromo-6-methoxynaphthalene (32p)

Methyl ether 32p was prepared according to the procedure for 32o usingnaphthol 37 (1.74 g, 7.80 mmol), NaOH (dissolved in 50 mL water, 624 mg,15.6 mmol), and dimethyl sulfate (1.48 mL, 15.6 mmol) in water (20 mL).Purification by flash column chromatography (hexanes to 90:10hexanes/EtOAc) afforded 32p as a white solid (1.38 g, 74% yield).R_(f)=0.49 (hexanes/EtOAc 90:10 v/v). ¹H NMR (400 MHz, CDCl₃) δ 8.14 (d,J=9.2 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.62 (d, J=7.4 Hz, 1H), 7.30-7.23(m, 2H), 7.13 (d, J=2.2 Hz, 1H), 3.94 (s, 3H). ¹³C NMR (101 MHz, CDCl₃)δ 158.3, 136.0, 128.9, 127.8, 127.6, 126.9, 126.9, 122.8, 120.1, 106.2,55.6.

2-Bromo-7-methoxynaphthalene (32q)

Methyl ether 32q was prepared according to the procedure for 32o using2-bromo-7-hydroxynaphthylene (482 mg, 2.16 mmol), NaOH (dissolved in 12mL water, 173 mg, 2.16 mmol), and dimethyl sulfate (0.41 mL, 4.3 mmol)in water (5 mL). 32q was obtained as a yellow solid (504 mg, 98% yield)and used in the next step without purification. R_(f)=0.66(hexanes/EtOAc 90:10 v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.90 (s, 1H), 7.70(d, J=8.8 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.40 (dd, J=8.6, 1.4 Hz, 1H),7.15 (dd, J=8.9, 2.3 Hz, 1H), 7.03 (d, J=1.7 Hz, 1H), 3.92 (s, 3H). ¹³CNMR (151 MHz, CDCl₃) δ 158.5, 136.0, 129.5, 129.4, 128.9, 127.5, 127.0,120.7, 119.3, 105.1, 55.5.

1-Ethyl-3-methoxynaphthalene (33o)

Magnesium turnings (139 mg, 5.72 mmol) were sealed in a vial and stirredvigorously at 90° C. under vacuum for 1 hour. The magnesium was flushedwith N₂ and brought to room temperature. Anhydrous THF (1 mL) was added,followed by a few drops of bromoethane to initiate the Grignardreaction. The contents were diluted with more anhydrous THF (8 mL), andbromoethane (0.30 mL, 4.1 mmol) was added dropwise over 30 minutes. Themixture was stirred until almost all the magnesium was consumed (about30 minutes). The Grignard solution was then transferred to a separatevial containing naphthyl bromide 32o (646 mg, 2.72 mmol) and NiCl₂(dppp)(73.8 mg, 0.136 mmol) under N₂ atmosphere, and the mixture was heated at60° C. for 3 hours. The reaction was quenched with MeOH (2 mL), and thesolvent was removed in vacuo. The residue was dissolved in EtOAc (125mL) and washed with brine (100 mL). The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. Purificationby flash column chromatography (hexanes to 95:5 hexanes/EtOAc) afforded33o as a yellow oil (401 mg, 79% yield). R_(f)=0.47 (hexanes/EtOAc 95:5v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J=8.3 Hz, 1H), 7.75 (d, J=8.1Hz, 1H), 7.47-7.41 (m, 1H), 7.40-7.34 (m, 1H), 7.05-7.98 (m, 2H), 3.92(s, 3H), 3.08 (q, J=7.5 Hz, 2H), 1.38 (t, J=7.5 Hz, 3H). ¹³C NMR (101MHz, CDCl₃) δ 157.4, 142.3, 135.3, 127.7, 127.7, 126.2, 123.8, 123.6,117.8, 104.1, 55.3, 25.8, 14.8. MS (ESI⁺) calculated for [C₁₃H₁₅O]⁺[M+H]⁺, 187.1; found 187.1.

1-Ethyl-6-methoxynaphthalene (33p)

Methyl ether 33p was prepared according to the procedure for 33o usingnaphthyl bromide 32p (500 mg, 2.11 mmol), NiCl₂(dppp) (57.2 mg, 0.105mmol), bromoethane (0.24 mL, 3.2 mmol), and magnesium turnings (108 mg,4.43 mmol) in anhydrous THF (8 mL). Purification by flash columnchromatography (hexanes to 95:5 hexanes/EtOAc) afforded 33p as a clearoil (328 mg, 84% yield). R_(f)=0.54 (hexanes/EtOAc 95:5 v/v). ¹H NMR(400 MHz, CDCl₃) δ 7.97 (d, J=8.9 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.37(app t, J=7.6 Hz, 1H), 7.22-7.15 (m, 3H), 3.93 (s, 3H), 3.08 (q, J=7.5Hz, 2H), 1.37 (t, J=7.5 Hz, 3H). ¹³C NMR (400 MHz, CDCl₃) δ 157.3,140.5, 135.2, 127.3, 126.5, 125.5, 125.4, 122.9, 118.4, 106.8, 55.4,26.1, 15.3. MS (ESI⁺) calculated for [C₁₃H₁₅O]⁺ [M+H]⁺, 187.1; found187.1.

2-Ethyl-7-methoxynaphthalene (33q)

Methyl ether 33q was prepared according to the procedure for 33o usingnaphthyl bromide 32q (600 mg, 2.53 mmol), NiCl₂(dppp) (68.6 mg, 0.127mmol), bromoethane (0.28 mL, 3.8 mmol), and magnesium turnings (129 mg,5.31 mmol) in anhydrous THF (9 mL). Purification by flash columnchromatography (hexanes to 95:5 hexanes/EtOAc) afforded 33q as a whitesolid (378 mg, 80% yield). R_(f)=0.42 (hexanes/EtOAc 95:5 v/v). ¹H NMR(400 MHz, CDCl₃) δ 7.70 (app s, 1H), 7.68 (s, 1H), 7.53 (s, 1H), 7.21(dd, J=8.3, 1.6 Hz, 1H), 7.10-7.06 (m, 2H), 3.92 (s, 3H), 2.80 (q, J=7.6Hz, 2H), 1.32 (t, J=7.6 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 157.9,142.5, 135.0, 129.2, 127.7, 127.6, 124.9, 124.7, 117.9, 105.6, 55.4,29.2, 15.7. MS (ESI⁺) calculated for [C₁₃H₁₅O]⁺ [M+H]⁺, 187.1; found187.1.

4-Ethylnaphthalen-2-ol (34o)

Naphthol 34o was prepared according to the procedure for 20 using methylether 33o (393 mg, 2.11 mmol) and boron tribromide (1M in DCM, 4.22 mL,4.22 mmol) in anhydrous DCM (10 mL). Purification by flash columnchromatography (hexanes to 75:25 hexanes/EtOAc) afforded 34o as anorange solid (304 mg, 83% yield). R_(f)=0.56 (hexanes/EtOAc 75:25 v/v).¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J=8.4 Hz, 1H), 7.69 (d, J=7.9 Hz,1H), 7.45-7.40 (m, 1H), 7.39-7.33 (m, 1H), 7.01 (d, J=2.4 Hz, 1H), 6.99(d, J=2.4 Hz, 1H), 4.84 (br s, 1H), 3.08 (q, J=7.5 Hz, 2H), 1.38 (t,J=7.5 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 153.1, 143.0, 135.3, 127.6,127.4, 126.3, 123.9, 123.6, 116.8, 107.8, 25.8, 14.9. MS (ESI⁺)calculated for [C₁₂H₁₃O]⁺ [M+H]⁺, 173.1; found 173.1.

5-ethylnaphthalen-2-ol (34p)

Naphthol 34p was prepared according to the procedure for 20 using methylether 33p (319 mg, 1.71 mmol) and boron tribromide (1M in DCM, 3.43 mL,3.43 mmol) in anhydrous DCM (10 mL). Purification by flash columnchromatography (hexanes to 75:25 hexanes/EtOAc) afforded 34p as a darkyellow oil (269 mg, 91% yield). R_(f)=0.48 (hexanes/EtOAc 75:25 v/v). ¹HNMR (400 MHz, CDCl₃) δ 7.98 (d, J=9.0 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H),7.36 (app t, J=7.6 Hz, 1H), 7.20 (d, J=7.0 Hz, 1H), 7.16 (d, J=2.2 Hz,1H), 7.13 (dd, J=9.0, 2.5 Hz, 1H), 4.92 (br s, 1H), 3.08 (q, J=7.5 Hz,2H), 1.37 (t, J=7.5 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 153.1, 140.6,135.3, 127.4, 126.7, 126.0, 125.1, 122.9, 117.4, 110.5, 26.1, 15.2. MS(ESI⁺) calculated for [C₁₂H₁₃O]⁺ [M+H]⁺, 173.1; found 173.1.

7-Ethylnaphthalen-2-ol (34q)

Naphthol 34q was prepared according to the procedure for 20 using methylether 33q (375 mg, 2.02 mmol) and boron tribromide (1M in DCM, 4.03 mL,4.03 mmol) in anhydrous DCM (17 mL). Purification by flash columnchromatography (hexanes to 75:25 hexanes/EtOAc) afforded 34q as apeach-colored solid (286 mg, 82% yield). R_(f)=0.53 (hexanes/EtOAc 75:25v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J=6.2 Hz, 1H), 7.69 (d, J=5.8Hz, 1H), 7.47 (s, 1H), 7.20 (dd, J=8.4, 1.6 Hz, 1H), 7.09 (d, J=2.4 Hz,1H), 7.03 (dd, J=8.8, 2.5 Hz, 1H), 4.83 (br s, 1H), 2.78 (q, J=7.6 Hz,2H), 1.32 (t, J=7.6 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 153.5, 142.7,135.0, 129.7, 127.8, 127.6, 125.1, 124.3, 116.9, 109.3, 29.2, 15.6. MS(ESI⁺) calculated for [C₁₂H₁₃O]⁺ [M+H]⁺, 173.1; found 173.1.

Synthesis of Naphthol Intermediate 37

5-Amino-2-hydroxynaphthalene-1-sulfonic acid (35)

This procedure was adapted from Everett et al.⁷ A flask containing5-amino-2-naphthol (3.00 g, 18.8 mmol) was heated to 55° C. before theaddition of fuming H₂SO₄ (10 mL). The mixture was stirred for 1 hour,removed from the heat, covered, and allowed to sit at room temperatureovernight. The contents were suspended in water (125 mL) and filtered.The solid was then taken up in acetone (70 mL), filtered again, washedwith more acetone (10 mL), and air-dried to afford 35 as a white solid(3.74 g, 83% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 12.19 (br s, 1H), 9.96(br s, 2H), 8.67 (d, J=8.8 Hz, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.49 (dd,J=8.7, 7.5 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.24 (d, J=9.2 Hz, 1H). ¹³CNMR (151 MHz, DMSO-d₆) δ 152.9, 131.7, 128.6, 126.0, 125.7, 124.8,121.9, 120.9, 120.4, 116.8. MS (ESI⁺) calculated for [C₁₀H₁₀NO₄S]⁺[M+H]⁺, 240.0; found 240.0.

5-Bromo-2-hydroxynaphthalene-1-sulfonic acid (36)

This procedure was adapted from Everett et al.⁷ To a flask containingfuming H₂SO₄ (2.75 mL, 51.6 mmol) and water (7.5 mL) cooled to 0° C. wasadded a solution of sulfonic acid 35 (3.74 g, 15.6 mmol), NaOH (644 mg,16.1 mmol), and NaNO₂ (1.07 g, 15.5 mmol) in water (30 mL) dropwisewithout allowing the temperature to exceed 5° C. The brownish-yellowprecipitate was filtered and washed with ice water. The moist filtercake was then added to a flask containing CuBr (2.27 g, 15.8 mmol),CuBr₂ (3.51 g, 15.7 mmol), and HBr (3.67 mL, 71.9 mmol) dissolved inwater (75 mL). The walls of the flask were washed with more water (25mL), and the mixture was heated at 70° C. for 1 hour before filtering.To the filtrate was added NaCl (65 g, 1.1 mol), and the mixture wasstirred at room temperature overnight. The precipitate was collected bysuction filtration and air-dried to afford 36 as a sand-colored solid(3.76 g, 79% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.17 (br s, 1H), 8.71(d, J=8.7 Hz, 1H), 8.05 (d, J=9.2 Hz, 1H), 7.65 (d, J=7.4 Hz, 1H), 7.36(dd, J=8.6, 7.6 Hz, 1H), 7.19 (d, J=9.2 Hz, 1H). ¹³C NMR (101 MHz,DMSO-d₆) δ 152.9, 132.2, 129.6, 126.9, 126.9, 126.0, 125.7, 121.7,121.7, 121.2. MS (ESI⁻) calculated for [C₁₀H₆BrO₄S]⁻ [M−H]⁻, 300.9;found 300.9.

5-Bromonaphthalen-2-ol (37)

This procedure was adapted from Everett et al.⁷ A suspension of sulfonicacid 36 (3.76 g, 12.4 mmol) in 20% (wt/wt) aqueous H₂SO₄ (75 mL) washeated at reflux for 20 minutes. After cooling to room temperature, thereaction mixture was extracted with diethyl ether (125 mL). The organicphase was washed with brine (75 mL), dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. Purification by flash columnchromatography (hexanes to 50:50 hexanes/EtOAc) afforded 37 as a brownsolid (1.74 g, 63% yield). R_(f)=0.81 (hexanes/EtOAc 50:50 v/v). ¹H NMR(400 MHz, CDCl₃) δ 8.16 (d, J=9.1 Hz, 1H), 7.66-7.60 (m, 2H), 7.28-7.23(m, 1H), 7.20 (dd, J=9.1, 2.5 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 4.96 (s,1H). ¹³C NMR (400 MHz, CDCl₃) δ 154.1, 136.0, 129.5, 127.9, 127.7,127.1, 126.5, 122.9, 119.1, 110.0. MS (ESI⁺) calculated for [C₁₀H₈BrO]⁺[M+H]⁺, 223.0; found 223.0.

Synthesis of Naphthol Intermediates 40r and 40s

1-Bromo-3-(methoxymethoxy)naphthalene (38r)

To a solution of naphthol 310 (542 mg, 2.43 mmol) anddiisopropylethylamine (0.47 mL, 2.7 mmol) in anhydrous DCM (12 mL)cooled to 0° C. was slowly added chloromethyl methyl ether (0.20 mL, 2.7mmol). The solution was warmed to room temperature and stirred for 14hours. The reaction mixture was diluted with EtOAc (100 mL) and washedwith brine (100 mL). The organic phase was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. Purification by flash columnchromatography (hexanes to 75:25 hexanes/EtOAc) afforded 38r as a yellowoil (528 mg, 81% yield). R_(f)=0.62 (hexanes/EtOAc 75:25 v/v). ¹H NMR(400 MHz, CDCl₃) δ 8.16-8.13 (m, 1H), 7.75-7.71 (m, 1H), 7.58 (d, J=2.3Hz, 1H), 7.51-7.43 (m, 2H), 7.39 (d, J=2.2 Hz, 1H), 5.28 (s, 2H), 3.52(s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 154.7, 135.2, 128.3, 127.6, 127.3,127.0, 125.5, 123.5, 123.2, 110.3, 94.8, 56.3.

1-Bromo-6-ethyl-3-(methoxymethoxy)naphthalene (38s)

Naphthyl bromide 38s was prepared according to the procedure for 38rusing naphthol 31s (404 mg, 1.61 mmol), diisopropylethylamine (0.31 mL,1.8 mmol), and chloromethyl methyl ether (0.13 mL, 1.8 mmol) inanhydrous DCM (9 mL). Purification by flash column chromatography(hexanes to 75:25 hexanes/EtOAc) afforded 38s as a purple oil (412 mg,87% yield). R_(f)=0.72 (hexanes/EtOAc 75:25 v/v). ¹H NMR (400 MHz,CDCl₃) δ 8.05 (d, J=8.6 Hz, 1H), 7.54-7.48 (m, 2H), 7.35-7.30 (m, 2H),5.27 (s, 2H), 3.51 (s, 3H), 2.80 (q, J=7.6 Hz, 2H), 1.31 (t, J=7.6 Hz,3H). ¹³C NMR (101 MHz, CDCl₃) δ 154.7, 143.4, 135.4, 127.0, 126.8,126.8, 125.4, 123.2, 122.2, 110.0, 94.8, 56.3, 28.9, 15.5.

1-Cyclopropyl-3-(methoxymethoxy)naphthalene (39r)

A mixture of naphthyl bromide 38r (521 mg, 1.95 mmol),cyclopropylboronic acid (218 mg, 2.53 mmol), K₃PO₄ (1.45 g, 6.82 mmol),tricyclohexylphosphine (54.6 mg, 0.195 mmol), toluene (9 mL), and water(0.6 mL) in a vial was degassed with N₂ for 7 minutes. Pd(OAc)₂ (21.9mg, 0.0974 mmol) was added, the vial was sealed, and the contents wereheated at 100° C. for 3 hours. The reaction mixture was then dilutedwith EtOAc (100 mL) and washed with brine (100 mL). The organic phasewas dried over anhydrous Na₂SO₄ and concentrated under reduced pressure.Purification by flash column chromatography (hexanes to 95:5hexanes/EtOAc) afforded 39r as a yellow oil (396 mg, 89% yield).R_(f)=0.37 (hexanes/EtOAc 95:5 v/v). ¹H NMR (400 MHz, CDCl₃) δ 8.32 (d,J=8.1 Hz, 1H), 7.75 (d, J=7.7 Hz, 1H), 7.48-7.39 (m, 2H), 7.26 (s, 1H),7.00 (d, J=2.3 Hz, 1H), 5.29 (s, 2H), 3.52 (s, 3H), 2.38-2.29 (m, 1H),1.10-1.04 (m, 2H), 0.81-0.75 (m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 154.8,141.5, 134.9, 129.8, 127.8, 126.3, 124.4, 124.0, 117.1, 108.3, 94.6,56.2, 13.3, 6.7. MS (ESI⁺) calculated for [C₁₅H₁₇O₂]⁺ [M+H]⁺, 229.1;found 229.1.

1-Cyclopropyl-6-ethyl-3-(methoxymethoxy)naphthalene (39s)

Cyclopropylnaphthalene 39s was prepared according to the procedure for39r using naphthyl bromide 38s (408 mg, 1.38 mmol), cyclopropylboronicacid (154 mg, 1.80 mmol), K₃PO₄ (1.03 g, 4.84 mmol),tricyclohexylphosphine (38.8 mg, 0.138 mmol), and Pd(OAc)₂ (15.5 mg,0.0691 mmol) in toluene (6 mL) and water (0.4 mL). Purification by flashcolumn chromatography (hexanes to 95:5 hexanes/EtOAc) afforded 39s as abrown oil (277 mg, 78% yield). R_(f)=0.39 (hexanes/EtOAc 95:5 v/v). ¹HNMR (400 MHz, CDCl₃) δ 8.23 (d, J=8.6 Hz, 1H), 7.54 (s, 1H), 7.29 (dd,J=8.6, 1.4 Hz, 1H), 7.20 (d, J=1.8 Hz, 1H), 6.94-6.90 (m, 1H), 5.27 (s,2H), 3.51 (s, 3H), 2.80 (q, J=7.6 Hz, 2H), 2.36-2.28 (m, 1H), 1.32 (t,J=7.6 Hz, 3H), 1.08-1.02 (m, 2H), 0.79-0.74 (m, 2H). ¹³C NMR (101 MHz,CDCl₃) δ 154.9, 142.3, 141.3, 135.2, 128.2, 125.6, 125.2, 124.4, 116.1,108.0, 94.6, 56.2, 29.1, 15.7, 13.3, 6.7. MS (ESI⁺) calculated for[C₁₇H₂₁O₂]⁺ [M+H]⁺, 257.1; found 257.1.

4-Cyclopropylnaphthalen-2-ol (40r)

To a solution of protected naphthylene 39r (392 mg, 1.72 mmol) in EtOH(4 mL) was added an emulsion of concentrated HCl (0.15 mL) in dioxane(3.85 mL). The mixture was stirred at room temperature for 2 hoursbefore the addition of another portion of concentrated HCl (0.15 mL).The contents were stirred for 17 more hours, diluted with diethyl ether(100 mL) and washed with brine (100 mL). The organic phase was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to afford40r as a red oil (316 mg, 99% yield). R_(f)=0.53 (hexanes/EtOAc 75:25v/v). ¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J=8.3 Hz, 1H), 7.68 (d, J=8.1Hz, 1H), 7.47-7.42 (m, 1H), 7.42-7.36 (m, 1H), 7.00 (d, J=2.2 Hz, 1H),6.89 (d, J=2.1 Hz, 1H), 4.99 (br s, 1H), 2.39-2.29 (m, 1H), 1.11-1.03(m, 2H), 0.81-0.72 (m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 153.1, 142.0,135.1, 129.2, 127.1, 126.5, 124.6, 123.6, 115.8, 107.9, 13.3, 6.8. MS(ESI⁺) calculated for [C₁₃H₁₃O]⁺ [M+H]⁺, 185.1; found 185.1.

4-Cyclopropyl-7-ethylnaphthalen-2-ol (40s)

Naphthol 40s was prepared according to the procedure for 40r usingprotected naphthalene 39s (275 mg, 1.07 mmol) and concentrated HCl (0.18mL) in EtOH (5 mL) and dioxane (4.91 mL). Purification by flash columnchromatography (hexanes to 75:25 hexanes/EtOAc) afforded 40s as a yellowoil (181 mg, 65% yield). R_(f)=0.48 (hexanes/EtOAc 75:25 v/v). ¹H NMR(400 MHz, CDCl₃) δ 8.22 (d, J=8.6 Hz, 1H), 7.47 (s, 1H), 7.30-7.24 (m,1H), 6.95 (s, 1H), 6.82 (s, 1H), 4.79 (s, 1H), 2.79 (q, J=7.5 Hz, 2H),2.37-2.28 (m, 1H), 1.33 (t, J=7.6 Hz, 3H), 1.09-1.02 (m, 2H), 0.79-0.73(m, 2H). ¹³C NMR (151 MHz, CDCl₃) δ 153.2, 142.5, 141.8, 135.3, 127.7,124.9, 124.8, 124.5, 114.9, 107.6, 29.1, 15.7, 13.3, 6.7. MS (ESI⁺)calculated for [C₁₅H₁₇O]⁺ [M+H]⁺, 213.1; found 213.1.

Synthesis of Naphthylamine Intermediate 44

4-(4-Ethylphenyl)butanoic acid (41)

To a solution of mercuric chloride (666 mg, 2.45 mmol) in water (7 mL)and concentrated HCl (20 mL) was slowly added zinc (6.66 g, 102 mmol).After bubbling subsided, additional portions of mercuric chloride (666mg, 2.45 mmol) and zinc (6.66 g, 102 mmol) were added. The contents werestirred for 30 minutes at room temperature. The liquid was decanted, andthe solid amalgam was washed twice with water. A solution of4-(4-ethylphenyl)-4-oxobutyric acid (3.00 g, 14.5 mmol) in toluene (7.5mL), water (15 mL), and concentrated HCl (15 mL) was then added to themercury-zinc amalgam. The mixture was heated at reflux for 17 hours,then filtered. The filtrate was diluted with EtOAc (200 mL) and washedwith brine (100 mL). The organic phase was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. Purification by flash columnchromatography (DCM to 25:75 DCM/EtOAc) afforded 41 as a white solid(2.04 g, 73% yield). R_(f)=0.27 (DCM/EtOAc 50:50 v/v). ¹H NMR (400 MHz,DMSO-d₆) δ 12.03 (br s, 1H), 7.11 (d, J=8.2 Hz, 2H), 7.08 (d, J=8.2 Hz,2H), 2.60-2.48 (m, 4H), 2.20 (t, J=7.4 Hz, 2H), 1.77 (app quint, J=7.5Hz, 2H), 1.16 (t, J=7.6 Hz, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ 174.3,141.1, 138.7, 128.2, 127.7, 34.0, 33.1, 27.8, 26.4, 15.7. MS (ESI⁺)calculated for [C₁₂H₁₅O]⁺ [M-OH]⁺, 175.1; found 175.1.

7-ethyl-3,4-dihydronaphthalen-1(2H)-one (42)

To a solution of carboxylic acid 41 (1.91 g, 9.93 mmol) and anhydrousDMF (7 drops) in anhydrous DCM (30 mL) cooled to 0° C. was added oxalylchloride (1.68 mL, 19.9 mmol) dropwise. The contents were stirred at 0°C. for 1 hour, then at room temperature for 1.5 hours. The mixture wascooled to 0° C., and aluminium chloride (2.65 g, 19.9 mmol) was added.The reaction was returned to room temperature, stirred for 18 hours, andquenched at 0° C. with 1N aqueous HCl (7 mL). The reaction mixture wasdiluted with EtOAc (200 mL) and washed with brine (100 mL). The organicphase was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. Purification by flash column chromatography (hexanes to 90:10hexanes/EtOAc) afforded 42 as a pale yellow oil (1.45 g, 84% yield).R_(f)=0.40 (hexanes/EtOAc 90:10 v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.88 (s,1H), 7.32 (d, J=9.1 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 2.93 (t, J=6.1 Hz,2H), 2.71-2.62 (m, 4H), 2.12 (app quint, J=6.4 Hz, 2H), 1.24 (t, J=7.6Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 198.8, 142.9, 142.0, 133.4, 132.6,128.9, 126.3, 39.4, 29.5, 28.6, 23.6, 15.7. MS (ESI⁺) calculated for[C₁₂H₁₅O]⁺ [M+H]⁺, 175.1; found 175.1.

7-Ethyl-3,4-dihydronaphthalen-1(2H)-one O-pivaloyl oxime (43)

This procedure was adapted from Hong et al.⁸ To a solution of tetralone42 (1.41 g, 8.08 mmol) in MeOH (25 mL) was added hydroxylaminehydrochloride (673 mg, 9.69 mmol) and NaOAc (1.59 g, 19.4 mmol). Thecontents were heated at reflux for 4 hours, monitoring formation of theoxime by mass spectrometry. The solvent was then removed in vacuo. Theresidue was dissolved in EtOAc (200 mL) and washed with brine (100 mL).The organic phase was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to afford the oxime intermediate, which was dissolvedin anhydrous DCM (40 mL) and cooled to 0° C. Triethylamine (3.38 mL,24.2 mmol) was added to the solution, followed by the dropwise additionof pivaloyl chloride (1.99 mL, 16.2 mmol). The mixture was stirred atroom temperature for 6 hours, then diluted with EtOAc (150 mL) andwashed with brine (75 mL). The organic phase was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. Purification by flashcolumn chromatography (hexanes to 90:10 hexanes/EtOAc) afforded 43 as acream-colored solid (2.20 g, 99% yield). R_(f)=0.50 (hexanes/EtOAc 90:10v/v). ¹H NMR (400 MHz, CDCl₃) δ 8.02 (s, 1H), 7.19 (d, J=7.8 Hz, 1H),7.09 (d, J=7.8 Hz, 1H), 2.85 (t, J=6.6 Hz, 2H), 2.75 (t, J=5.7 Hz, 2H),2.63 (q, J=7.6 Hz, 2H), 1.88 (app quint, J=6.4 Hz, 2H), 1.34 (s, 9H),1.22 (t, J=8.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 175.4, 162.5, 142.8,138.4, 130.7, 128.9, 128.7, 125.0, 39.1, 29.4, 28.7, 27.5, 25.8, 21.6,15.9. MS (ESI⁺) calculated for [C₁₇H₂₄NO₂]⁺ [M+H]⁺, 274.2; found 274.2.

7-ethylnaphthalen-1-amine (44)

A mixture of protected oxime 43 (2.20 g, 8.05 mmol), Pd(OAc)₂ (181 mg,0.805 mmol), tricyclohexylphosphine (451 mg, 1.61 mmol), K₂CO₃ (4.45 g,32.2 mmol), pivalic acid (247 mg, 2.41 mmol), and anhydrous toluene (40mL) were degassed with N₂ for 7 minutes and heated at 95° C. for 16hours. The reaction mixture was filtered through a pad of basic alumina.The filtrate was diluted with EtOAc (200 mL) and washed with brine (100mL). The organic phase was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. Purification by flash column chromatography(hexanes to 75:25 hexanes/EtOAc) afforded 44 as a deep red oil (1.10 g,80% yield). R_(f)=0.21 (hexanes/EtOAc 90:10 v/v). ¹H NMR (400 MHz,CDCl₃) δ 7.74 (d, J=8.4 Hz, 1H), 7.60 (s, 1H), 7.34 (dd, J=8.4, 1.4 Hz,1H), 7.30 (d, J=8.1 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 6.77 (d, J=7.2 Hz,1H), 4.12 (br s, 2H), 2.84 (q, J=7.6 Hz, 2H), 1.34 (t, J=7.6 Hz, 3H).¹³C NMR (101 MHz, CDCl₃) δ 141.7, 141.0, 133.0, 128.7, 127.1, 125.5,124.0, 119.0, 118.8, 110.0, 29.5, 15.9. MS (ESI⁺) calculated for[C₁₂H₁₄N]⁺ [M+H]⁺, 172.1; found 172.1.

Synthesis of Biphenyl Intermediates 45v and 45w

3′,5′-Dimethyl-[1,1′-biphenyl]-3-ol (45v)

A mixture of 3-iodophenol (502 mg, 2.28 mmol),3,5-dimethylbenzeneboronic acid (342 mg, 2.28 mmol), K₂CO₃ (1.26 g, 9.13mmol), Pd (10% by weight on carbon, 48.6 mg, 0.0456 mmol), and water (15mL) in a sealed vial was degassed with N₂ for 7 minutes and heated at80° C. for 2.5 hours. The reaction mixture was diluted with EtOAc (125mL) and washed with brine (100 mL). The organic phase was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. Purificationby flash column chromatography (hexanes to 75:25 hexanes/EtOAc) afforded45v as a clear oil (452 mg, 99% yield). R_(f)=0.46 (hexanes/EtOAc 75:25v/v). ¹H NMR (400 MHz, CDCl₃) δ 7.29 (app t, J=7.9 Hz, 1H), 7.19 (s,2H), 7.18-7.14 (m, 1H), 7.05 (app t, J=2.0 Hz, 1H), 7.00 (s, 1H), 6.80(dd, J=8.0, 2.5 Hz, 1H), 4.77 (br s, 1H), 2.38 (s, 6H). ¹³C NMR (101MHz, CDCl₃) δ 155.9, 143.4, 140.9, 138.4, 130.0, 129.3, 125.2, 120.0,114.2, 114.1, 21.5. MS (ESI⁺) calculated for [C₁₄H₁₅O]⁺ [M+H]⁺, 199.1;found 199.1.

4′-Ethoxy-[1,1′-biphenyl]-3-ol (45w)

Phenol 45w was prepared according to the procedure for 45v using3-iodophenol (510 mg, 2.32 mmol), 4-ethoxyphenylboronic acid (385 mg,2.32 mmol), K₂CO₃ (1.28 g, 9.27 mmol), and Pd (10% by weight on carbon,49.3 mg, 0.0464 mmol) in water (15 mL). Purification by flash columnchromatography (hexanes to 75:25 hexanes/EtOAc) afforded 45w as a whitesolid (454 mg, 91% yield). R_(f)=0.36 (hexanes/EtOAc 75:25 v/v). ¹H NMR(400 MHz, CDCl₃) δ 7.52-7.47 (m, 2H), 7.29 (d, J=7.9 Hz, 1H), 7.13 (d,J=7.7 Hz, 1H), 7.02 (app t, J=2.1 Hz, 1H), 6.98-6.93 (m, 2H), 6.77 (dd,J=8.4, 2.1 Hz, 1H), 4.82 (br s, 1H), 4.08 (q, J=7.0 Hz, 2H), 1.44 (t,J=7.0 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 158.8, 156.0, 142.8, 133.2,130.1, 128.2, 119.5, 114.9, 113.8, 113.7, 63.7, 15.0. MS (ESI⁺)calculated for [C₁₄H₁₅O₂]⁺ [M+H]⁺, 215.1; found 215.1.

Synthesis of Biphenyl Intermediate 48

4-(3-bromopropyl)morpholine (46)

To a solution of 3-morpholinopropanol (1.20 g, 8.26 mmol) in anhydrousDCM (40 mL) cooled to −18° C. was added tetrabromomethane (2.74 g, 8.26mmol) in four equivalent portions. The mixture was stirred at −18° C.for 15 minutes before the addition of triphenylphosphine (2.17 g, 8.26mmol) in four equivalent portions. The reaction was brought to roomtemperature and stirred for 2.5 hours. Water (40 mL) was added, and themixture was stirred vigorously for a few minutes. The layers wereallowed to separate, and the organic phase was washed with 1N HCl (50mL). The acid layer was neutralized with 1N NaOH (50 mL), and thenwashed with EtOAc (100 mL). The organic phase was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford 46 as a whitesolid (1.09 g, 63% yield). R_(f)=0.14 (hexanes/EtOAc 50:50 v/v). ¹H NMR(400 MHz, CDCl₃) δ 3.71 (t, J=4.5 Hz, 4H), 3.47 (t, J=6.6 Hz, 2H),2.53-2.41 (m, 6H), 2.03 (app quint, J=6.8 Hz, 2H). ¹³C NMR (101 MHz,CDCl₃) δ 67.1, 57.0, 53.8, 31.7, 29.7. MS (ESI⁺) calculated for[C₇H₁₅BrNO]⁺ [M+H]⁺, 208.0; found 208.0.

4-(3-(4-Iodophenoxy)propyl)morpholine (47)

To a solution of bromide 46 (810 mg, 3.89 mmol) and 4-iodophenol (779mg, 3.54 mmol) in anhydrous DMF (7 mL) was added K₂CO₃ (731 mg, 5.31mmol). The contents were heated at 80° C. for 15 hours. The reactionmixture was diluted with EtOAc (100 mL) and washed with brine (100 mL).The organic phase was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. Purification by flash column chromatography (85:15hexanes/EtOAc to EtOAc) afforded 47 as a white solid (1.07 g, 87%yield). R_(f)=0.13 (hexanes/EtOAc 50:50 v/v). ¹H NMR (400 MHz, CDCl₃) δ7.54 (d, J=8.3 Hz, 2H), 6.68 (d, J=8.3 Hz, 2H), 3.99 (t, J=6.3 Hz, 2H),3.72 (t, J=4.3 Hz, 4H), 2.50 (t, J=7.3 Hz, 2H), 2.48-2.43 (m, 4H), 1.95(app quint, J=6.6 Hz, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 159.0, 138.3,117.1, 82.7, 67.2, 66.4, 55.6, 53.9, 26.5. MS (ESI⁺) calculated for[C₁₃H₁₉INO₂]⁺ [M+H]⁺, 348.0; found 348.0.

4′-(3-Morphohnopropoxy)-[1,1′-biphenyl]-3-ol (48)

Phenol 48 was prepared according to the procedure for 45v using phenyliodide 47 (1.07 g, 3.08 mmol), 3-hydroxybenzeneboronic acid (425 mg,3.08 mmol), K₂CO₃ (1.70 g, 12.3 mmol), and Pd (10% by weight on carbon,65.6 mg, 0.0616 mmol) in water (30 mL). Purification by flash columnchromatography (DCM to EtOAc with 2% MeOH throughout) afforded 48 as awhite solid (671 mg, 70% yield). R_(f)=0.24 (DCM/EtOAc/MeOH 47.5:47.5:5v/v/v). ¹H NMR (400 MHz, DMSO-d₆) δ 9.44 (br s, 1H), 7.51 (d, J=8.6 Hz,2H), 7.21 (app t, J=7.8 Hz, 1H), 7.05-6.93 (m, 4H), 6.70 (dd, J=8.1, 1.5Hz, 1H), 4.04 (t, J=6.5 Hz, 2H), 3.58 (t, J=4.3 Hz, 4H), 2.49-2.24 (m,6H), 1.89 (app quint, J=6.5 Hz, 2H). ¹³C NMR (101 MHz, DMSO-d₆) δ 158.2,157.7, 141.3, 132.6, 129.8, 127.6, 116.9, 114.8, 113.7, 113.0, 66.2,65.8, 54.8, 53.3, 25.8. MS (ESI⁺) calculated for [C₁₉H₂₄NO₃]⁺ [M+H]⁺,314.2; found 314.1.

In order to facilitate further study of the in vitro and in vivo biologyof MIF, series of potent MIF tautomerase inhibitors have been pursued.Starting from a 113-μM docking hit, a novel series, which features apyrazole instead of a phenol, was optimized to yield compounds withK_(i) values as low as 60-70 nM. The optimization was greatlyfacilitated by molecular modeling and the ability to obtain multiplehigh-resolution crystal structures, which guided the effective selectionand placement of substituents. Recognition of the potential benefit ofaddition of a fluorine in the pyrazole ring also provided an essentialboost along with a synthetic challenge.

The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein by reference intheir entirety. While this invention has been disclosed with referenceto specific embodiments, it is apparent that other embodiments andvariations of this invention may be devised by others skilled in the artwithout departing from the true spirit and scope of the invention. Theappended claims are intended to be construed to include all suchembodiments and equivalent variations.

1. A compound of formula (I), or a salt, solvate, stereoisomer, or tautomer thereof, or any mixtures thereof:

wherein: Y is selected from the group consisting of a bond, —CH₂—, —O—, —S—, —S(═O)—, —S(═O)₂, and —N(R₂)—; R₁ is selected from the group consisting of H, C₁-C₆ alkyl, phenyl, naphthyl, tetrahydronaphthyl, phenanthryl, bicyclic heteroaryl, 1,2-dihydroacenaphthyl, acenaphthyl, adamantyl, (heteroaryl)-phenyl, and biphenyl; R₂ is selected from the group consisting of H and C₁-C₆ alkyl; Z is selected from the group consisting of —C(═O)OR, —S(═O)R, —S(═O)₂R, and S(═O)₂NRR; X is selected from the group consisting of H, C₁-C₃ alkyl, and halogen; wherein the phenyl, naphthyl, tetrahydronaphthyl, phenanthryl, bicyclic heteroaryl, 1,2-dihydroacenaphthyl, acenaphthyl, adamantyl, (heteroaryl)-phenyl, or biphenyl is independently optionally substituted with at least one group independently selected from the group consisting of halogen, —OH, —C(═O)OR, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkoxy, C₃-C₆ halocycloalkyl, C₃-C₆ halocycloalkoxy, —(CH₂)₁₋₆NRR, —O(CH₂)₁₋₆NRR, —(CH₂)₁₋₆NR(C₁-C₆ acyl), —O(CH₂)₁₋₆NR(C₁-C₆ acyl), —(CH₂)₁₋₆OR, —O(CH₂)₁₋₆OR, —(CH₂)₁₋₆C(═O)OR, —O(CH₂)₁₋₆C(═O)OR, —(CH₂)₁₋₆OR, —O(CH₂)₁₋₆OR, —(OCH₂CH₂)₁₋₆NRR, and —(OCH₂CH₂)₁₋₆C(═O)OR; wherein each occurrence of R is independently selected from the group consisting of H and C₁-C₆ alkyl, or two R groups combine with the N atom to which they are both bound to form a 3-8 membered heterocyclyl or heteroaryl group; and wherein, if R₁—Y is H, then Z cannot be —C(═O)OH.
 2. The compound of claim 1, which is a compound of formula (6):


3. The compound of claim 2, wherein R₁ is selected from the group consisting of phenyl and naphthyl.
 4. The compound of claim 2, which is selected from the group consisting of:


5. The compound of claim 1, which is a compound of formula (7):


6. The compound of claim 5, wherein R₁ is selected from the group consisting of phenyl and naphthyl.
 7. The compound of claim 5, wherein R₂ is methyl.
 8. The compound of claim 5, which is selected from the group consisting of:


9. The compound of claim 1, which is a compound of formula (8):


10. The compound of claim 9, wherein R₁ is selected from the group consisting of methylphenyl, methoxyphenyl, fluorophenyl, ethylnapthyl, cyclopropylnaphthyl, methylbiphenyl, ethoxybiphenyl, and N-morpholinopropoxybiphenyl.
 11. The compound of claim 9, wherein X is fluorine.
 12. The compound of claim 9, which is selected from the group consisting of:


13. A pharmaceutical composition comprising the compound of claim 1 and at least one pharmaceutically acceptable excipient.
 14. A method of treating or ameliorating an inflammatory disease, a neurological disorder, or cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of claim
 1. 15. The method of claim 14, wherein the inflammatory disease is rheumatoid arthritis, Crohn's disease, or inflammatory bowel syndrome.
 16. The method of claim 14, wherein the neurological disorder is schizophrenia.
 17. The method of claim 14, wherein the cancer is colorectal, lung, breast, or prostate.
 18. A method of inhibiting macrophage migration inhibitory factor in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of claim
 1. 19. A method of treating or ameliorating a disease or disorder associated with upregulated and/or dysregulated macrophage migration inhibitory factor expression in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of claim
 1. 